Abstract:

The present invention concerns substituted pyrazinone derivatives
according to the general Formula (I)
a pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof, an N-oxide form thereof or a
quaternary ammonium salt thereof, wherein the variables are defined in
Claim 1, having selective α2C-adrenoceptor antagonist
activity. It further relates to their preparation, compositions
comprising them and their use as a medicine. The compounds according to
the invention are useful for the prevention and/or treatment of central
nervous system disorders, mood disorders, anxiety disorders,
stress-related disorders associated with depression and/or anxiety,
cognitive disorders, personality disorders, schizoaffective disorders,
Parkinson's disease, dementia of the Alzheimer's type, chronic pain
conditions, neurodegenerative diseases, addiction disorders, mood
disorders and sexual dysfunction.

Claims:

1. Compound according to the general Formula (I)a pharmaceutically
acceptable acid or base addition salt thereof, a stereochemically
isomeric form thereof, an N-oxide form thereof or a quaternary ammonium
salt thereof, wherein:V is a naphthyl-radical, wherein one CH-unit in the
napthyl-moiety may optionally be replaced by a N-atom;Y is a bivalent
radical of Formula (II)whereinA is a nitrogen or a carbon-atomm is an
integer equal to zero, 1 or 2R4 is selected from the group of
hydrogen; alkyl and phenylcarboxylalkyl;R5 is selected from the
group of hydrogen and haloX1, X2 are each, independently from
each other, a covalent bond, a saturated or an unsaturated
(C1-8)-hydrocarbon radical, wherein one or more bivalent
--CH2-units and/or one or more monovalent CH3-units may
optionally be replaced by a respective bivalent or monovalent
phenyl-unit; and wherein one or more hydrogen atoms may be replaced by a
radical selected from the group of oxo; (C1-3)alkyloxy; halo; cyano;
nitro; formyl; hydroxy; amino; trifluoromethyl; mono- and
di((C1-3)alkyl)amino; carboxy; and thio;p, q are each, independently
from each other, an integer equal to 1 or 2;Q1, Q2 are each,
independently from each other, a radical selected from the group of
hydrogen; --NR1R2; Pir; --OR3 and Het; wherein two
radicals --OR3 may be taken together to form a bivalent radical
--O--(CH2)r--O-- wherein r is an integer equal to 1, 2 or
3;R1 and R2 are each, independently from each other, a radical
selected from the group of hydrogen; alkyl; alkenyl; alkynyl; aryl;
arylalkyl; alkylcarbonyl; alkenylcarbonyl; alkyloxy; alkyloxyalkyl;
alkyloxycarbonyl; alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; alkylsulfonyl; arylcarbonyl; aryloxyalkyl;
arylalkylcarbonyl; arylsulfonyl; Het; Het-alkyl; Het-alkylcarbonyl;
Het-carbonyl; Het-carbonylalkyl; alkyl-NRaRb;
carbonyl-NRaRb; carbonylalkyl-NRaRb;
alkylcarbonyl-NRaRb; and alkylcarbonylalkyl-NRaRb;
wherein Ra and Rb are each independently selected from the
group of hydrogen, alkyl, alkylcarbonyl, alkyloxyalkyl,
alkyloxycarbonylalkyl, aryl, arylalkyl, Het and alkyl-NRcRd,
wherein Rc and Rd are each independently from each other
hydrogen or alkyl;Pir is a radical containing at least one N, by which it
is attached to the X-radical, selected from the group of pyrrolidinyl;
imidazolidinyl; pyrazolidinyl; piperidinyl; piperazinyl; pyrrolyl;
pyrrolinyl; imidazolinyl; pyrrazolinyl; pyrrolyl; imidazolyl; pyrazolyl;
triazolyl; azepyl; diazepyl; morpholinyl; thiomorpholinyl; indolyl;
isoindolyl; indolinyl; indazolyl; benzimidazolyl; and
1,2,3,4-tetrahydro-isoquinolinyl; wherein each Pir-radical is optionally
substituted by 1, 2 or 3 radicals selected from the group of hydroxy;
halo; oxo; (C1-3)alkyl; trifluoromethyl phenyl; benzyl;
pyrrolidinyl; and pyridinyloxy;R3 is a radical selected from the
group of hydrogen; alkyl; aryl arylalkyl; Het; and Het-alkyl;Het is a
heterocyclic radical selected from the group of pyrrolidinyl
imidazolidinyl; pyrazolidinyl; piperidinyl; piperazinyl; pyrrolyl
pyrrolinyl; imidazolinyl; pyrrazolinyl; pyrrolyl; imidazolyl pyrazolyl;
triazolyl; pyridinyl; pyridazinyl; pyrimidinyl; pyrazinyl; triazinyl;
azepyl; diazepyl; morpholinyl; thiomorpholinyl indolyl; isoindolyl;
indolinyl; indazolyl; benzimidazolyl 1,2,3,4-tetrahydro-isoquinolinyl;
furyl; thienyl; oxazolyl; isoxazolyl; thiazolyl; thiadiazolyl;
isothiazolyl; dioxolyl; dithianyl tetrahydrofuryl; tetrahydropyranyl;
quinolinyl; isoquinolinyl quinoxalinyl; benzoxazolyl; benzisoxazolyl;
benzothiazolyl benzisothiazolyl; benzofuranyl; benzothienyl;
benzopiperidinyl; chromenyl; and imidazo[1,2-a]pyridinyl; wherein each
Het-radical is optionally substituted by one or more radicals selected
from the group of halo; oxo; (C1-3)alkyl; (C1-3)alkylcarbonyl;
(C1-3)alkenylthio; imidazolyl-(C1-3)alkyl and
(C1-3)alkyloxycarbonyl;aryl is naphthalenyl or phenyl, each
optionally substituted with 1, 2 or 3 substituents, each independently
from each other, selected from the group of oxo; (C1-3)alkyl;
(C1-3)alkyloxy; halo; cyano; nitro; formyl; hydroxy; amino;
trifluoromethyl; mono- and di((C1-3)alkyl)amino; carboxy; and
thio;alkyl is a straight or branched saturated hydrocarbon radical having
from 1 to 8 carbon atoms; or is a cyclic saturated hydrocarbon radical
having from 3 to 7 carbon atoms; or is a cyclic saturated hydrocarbon
radical having from 3 to 7 carbon atoms attached to a straight or
branched saturated hydrocarbon radical having from 1 to 8 carbon atoms;
wherein each radical is optionally substituted on one or more carbon
atoms with one or more radicals selected from the group of oxo;
(C1-3)alkyloxy; halo; cyano; nitro; formyl; hydroxy; amino; carboxy;
and thio;alkenyl is an alkyl radical as defined above, further having one
or more double bonds;alkynyl is an alkyl radical as defined above,
further having one or more triple bonds; andarylalkyl is an alkyl radical
as defined above, further having one or more CH3-groups replaced by
phenyl.

2. Compound according to claim 1, characterized in that V is selected from
the group of radicals (z-1), (z-2), (z-3), (z-4), (z-5) and (z-6).

3. Compound according to any one of claims 1 and 2, characterized in that
A is a carbon atom, m is zero and R4 is hydrogen.

4. Compound according to any one of claims 1 to 3, characterized in that
the moiety --CH2--Y-- is attached to V by the atom, denoted by "a".

5. Compound according to any one of claims 1 to 4, characterized in that
R5 is chloro.

6. Compound according to any one of claims 1 to 5, characterized in that
each of X1 and X2, independently from each other, are selected
from the group of a covalent bond; --CH2--; --CH2CH2--;
--CH2CH2CH2--; --CH2CH2CH2CH2--;
--CH2CH═CHCH2--; --CH2C≡CCH2--;
--CH(CH3)CH(CH3)--; --C(═O)CH2--;
--C(═O)CH2CH2--; --C(═O)CH2CH2CH2--;
--CH2C(═O)--; --CH2CH2C(═O)--;
--CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--;
--CH2CH2C(═O)CH2--; --C6H4--;
--CH2C6H4--; --CH2CH2C6H4--;
--CH2CH2CH2C6H4--; --C6H4CH2--;
--C6H4CH2CH2--;
--C6H4CH2CH2CH2--;
--CH2C6H4CH2--,
--CH2CH2C6H4CH2CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H.sub.4--.

7. Compound according to any one of claims 1 to 6, characterized in that
each of X1 and X2, independently from each other, are selected
from the group of a covalent bond; --CH2--; --CH2CH2--;
--CH2CH2CH2--; --CH2CH2CH2CH2--;
--CH2CH═CHCH2--; --CH2C≡CCH2--;
--CH2C(═O)--; --CH2CH2C(═O)--;
--CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--; --C6H4--;
--CH2C6H4--; --CH2CH2CH2C6H4--;
--C6H4CH2--; --CH2C6H4CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H.sub.4--.

8. Compound according to any one of claims 1 to 7, characterized in that
one or more hydrogen atoms in each of X1 and X2 are optionally
replaced by a radical selected from the group of oxo;
(C1-3)alkyloxy; halo; cyano; nitro; and formyl.

9. Compound according to any one of claims 1 to 8, characterized in that
X1 is a covalent bond, Q1 is hydrogen and p is 1.

10. Compound according to any one of claims 1 to 9, characterized in that
R1 and R2 are each, independently from each other, a radical
selected from the group of hydrogen; alkyl; alkenyl; alkynyl; aryl;
arylalkyl; alkylcarbonyl; alkenylcarbonyl; alkyloxyalkyl;
alkyloxycarbonyl; alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; arylcarbonyl; aryloxyalkyl;
arylalkylcarbonyl; Het-alkyl; Het-alkylcarbonyl; Het-carbonyl;
Het-carbonylalkyl; alkyl-NRaRb; carbonyl-NRaRb;
carbonylalkyl-NRaRb alkylcarbonyl-NRaRb; and
alkylcarbonylalkyl-NRaRb; wherein each of Ra and Rb
independently are selected from the group of hydrogen, alkyl,
alkylcarbonyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, arylalkyl, Het
and alkyl-NRaRb, wherein Rc and Rd are each
independently from each other hydrogen or alkyl.

11. Compound according to any one of claims 1 to 10, characterized in that
Pir is a radical containing at least one N, by which it is attached to
the X-radical, selected from the group of pyrrolidinyl; piperidinyl;
piperazinyl imidazolyl; morpholinyl; isoindolyl; wherein each Pir-radical
is optionally substituted by 1, 2 or 3 radicals selected from the group
of hydroxy; halo; oxo; (C1-3)alkyl; trifluoromethyl; phenyl; benzyl;
pyrrolidinyl; and pyridinyloxy.

12. Compound according to any one of claims 1 to 11, characterized in that
Het is a heterocyclic radical selected from the group of piperidinyl
piperazinyl; triazolyl; pyridinyl; pyrimidinyl; morpholinyl; indolyl;
furyl thienyl; isoxazolyl; thiazolyl; tetrahydrofuryl; tetrahydropyranyl;
quinolinyl; isoquinolinyl; benzofuranyl; benzothienyl; and
benzopiperidinyl; wherein each Het-radical is optionally substituted by
one or more radicals selected from the group of oxo; (C1-3)alkyl;
(C1-3)alkylcarbonyl; and imidazolyl-(C1-3)alkyl.

13. Compound according to any one of claims 1 to 12, characterized in that
aryl is phenyl, optionally substituted with 1, 2 or 3 substituents, each
independently from each other, selected from the group of
(C1-3)alkyl; halo; and trifluoromethyl.

14. Compound according to claim 1, characterized in that:V is selected
from the group of radicals (z-1), (z-2), (z-3), (z-5) and (z-6); wherein
the moiety --CH2--Y-- is attached to V by the atom, denoted by "a";Y
is a bivalent radical of Formula (II) wherein A is a nitrogen or a
carbon-atom; m is an integer equal to zero or 2; and R4 is selected
from the group of hydrogen; alkyl and phenylcarboxylalkyl;R5 is
selected from the group of hydrogen and halo;X1, X2 are each,
independently from each other, are selected from the group of a covalent
bond; --CH2--; --CH2CH2--; --CH2CH2CH2--;
--CH2CH2CH2CH2--; --CH2CH═CHCH2--;
--CH2C≡CCH2--; --CH2C(═O)--;
--CH2CH2C(═O)--; --CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--; --C6H4--;
--CH2C6H4--; --CH2CH2CH2C6H4--;
--C6H4CH2--; --CH2C6H4CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H4--; and wherein one or more
hydrogen atoms may be replaced by a radical selected from the group of
oxo; (C1-3)alkyloxy; halo; cyano; nitro; and formyl;p, q are each,
independently from each other, an integer equal to 1 or 2;Q1,
Q2 are each, independently from each other, a radical selected from
the group of hydrogen; --NR1R2; Pir; --OR3 and Het;
wherein two radicals --OR3 may be taken together to form a bivalent
radical --O--(CH2)r--O-- wherein r is an integer equal to 1, 2
or 3;R1 and R2 are each, independently from each other, a
radical selected from the group of hydrogen; alkyl; alkenyl; alkynyl;
aryl arylalkyl; alkylcarbonyl; alkenylcarbonyl; alkyloxyalkyl
alkyloxycarbonyl; alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; arylcarbonyl; aryloxyalkyl
arylalkylcarbonyl; Het-alkyl; Het-alkylcarbonyl; Het-carbonyl
Het-carbonylalkyl alkyl; --NRaRb carbonyl-NRaRb;
carbonylalkyl-N RaRb; alkylcarbonyl-NRaRb; and
alkylcarbonylalkyl-NRaRb wherein Ra and Rb are each
independently selected from the group of hydrogen, alkyl, alkylcarbonyl,
alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, arylalkyl, Het and
alkyl-NRcRd wherein Rc and Rd are each independently
from each other hydrogen or alkyl;Pir is a radical containing at least
one N, by which it is attached to the X-radical, selected from the group
of pyrrolidinyl; piperidinyl; piperazinyl; imidazolyl; morpholinyl;
isoindolyl; wherein each Pir-radical is optionally substituted by 1, 2 or
3 radicals selected from the group of hydroxy; halo; oxo;
(C1-3)alkyl; trifluoromethyl phenyl; benzyl; pyrrolidinyl; and
pyridinyloxy;R3 is a radical selected from the group of hydrogen;
alkyl; aryl; arylalkyl; Het; and Het-alkyl;Het is a heterocyclic radical
selected from the group of piperidinyl piperazinyl; triazolyl; pyridinyl;
pyrimidinyl; morpholinyl; indolyl furyl; thienyl; isoxazolyl; thiazolyl;
tetrahydrofuryl; tetrahydropyranyl; quinolinyl; isoquinolinyl;
benzofuranyl; benzothienyl; and benzopiperidinyl; wherein each
Het-radical is optionally substituted by one or more radicals selected
from the group of oxo; (C1-3)alkyl; (C1-3)alkylcarbonyl; and
imidazolyl-(C1-3)alkyl;aryl is phenyl, optionally substituted with
1, 2 or 3 substituents, each independently from each other, selected from
the group of (C1-3)alkyl; halo; and trifluoromethyl;alkyl is a
straight or branched saturated hydrocarbon radical having from 1 to 8
carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3
to 7 carbon atoms; or is a cyclic saturated hydrocarbon radical having
from 3 to 7 carbon atoms attached to a straight or branched saturated
hydrocarbon radical having from 1 to 8 carbon atoms; wherein each radical
is optionally substituted on one or more carbon atoms with one or more
radicals selected from the group of oxo; (C1-3)alkyloxy; halo;
cyano; nitro; formyl; hydroxy; amino; carboxy; and thio;alkenyl is an
alkyl radical as defined above, further having one or more double
bonds;alkynyl is an alkyl radical as defined above, further having one or
more triple bonds; andarylalkyl is an alkyl radical as defined above,
further having one or more CH3-groups replaced by phenyl.

15. Compound according to any one of claims 1 to 14 for use as a medicine.

16. Pharmaceutical composition comprising a pharmaceutically acceptable
carrier or diluent and, as active ingredient, a therapeutically effective
amount of a compound according to any one of claims 1 to 14.

17. Pharmaceutical composition according to claim 16, characterized in
that is comprises further one or more other compounds selected from the
group of antidepressants, anxiolytics and antipsychotics.

18. Pharmaceutical composition according to any of claims 16 and 17,
characterized in that it is in a form suitable to be orally administered.

19. Process for the preparation of a pharmaceutical composition as claimed
in claim 16, characterized in that a pharmaceutically acceptable carrier
is intimately mixed with a therapeutically effective amount of a compound
as claimed in any one of claims 1 to 14.

20. Process for the preparation of a pharmaceutical composition as claimed
in claim 17, characterized in that a pharmaceutically acceptable carrier
is intimately mixed with a therapeutically effective amount of a compound
as claimed in any one of claims 1 to 14 and one or more other compounds
selected from the group of antidepressants, anxiolytics and
antipsychotics.

21. Use of a compound according to any one of claims 1 to 14 for the
preparation of a medicament for the prevention and/or treatment of
diseases where antagonism of the α2-adrenergic receptor, in
particular antagonism of the α2C-adrenergic receptor is of
therapeutic use.

22. Use of a compound according to any one of claims 1 to 14 for the
preparation of a medicament for the prevention and/or treatment of
central nervous system disorders, mood disorders, anxiety disorders,
stress-related disorders associated with depression and/or anxiety,
cognitive disorders, personality disorders, schizoaffective disorders,
Parkinson's disease, dementia of the Alzheimer's type, chronic pain
conditions, neurodegenerative diseases, addiction disorders, mood
disorders and sexual dysfunction.

23. Use of a compound according to any one of claims 1 to 14 in
combination with one or more other compounds selected from the group of
antidepressants, anxiolytics and antipsychotics for the preparation of a
medicament for the prevention and/or treatment of central nervous system
disorders, mood disorders, anxiety disorders, stress-related disorders
associated with depression and/or anxiety, cognitive disorders,
personality disorders, schizoaffective disorders, Parkinson's disease,
dementia of the Alzheimer's type, chronic pain conditions,
neurodegenerative diseases, addiction disorders, mood disorders and
sexual dysfunction.

[0002]The present invention concerns substituted pyrazinone derivatives
having selective α2C-adrenoceptor antagonist activity, as well
as having 5-HT reuptake inhibition activity. It further relates to their
preparation, pharmaceutical compositions comprising them and their use as
a medicine, especially for the treatment of central nervous system
disorders.

BACKGROUND OF THE INVENTION

[0003]Adrenergic receptors form the interface between the endogenous
catecholamines epinephrine and norepinephrine and a wide array of target
cells in the body to mediate the biological effects of the sympathetic
nervous system. They are divided into three major subcategories,
α1, α2 and β. To date, nine distinct
adrenergic receptor subtypes have been cloned from several species:
α1A, α1B, α1D, α2A,
α2B, α2C, β1, β2 and
β3 (Hieble, J. P.; et al. J. Med. Chem. 1995, 38, 3415-3444).
Available α2 ligands have only marginal subtype selectivity. A
complicating factor is that α2-adrenoceptor ligands, which are
imidazoles or imidazolines, also bind with moderate-to-high affinity to
non-adrenoceptor imidazoline binding sites.

[0004]The three α2-adrenoceptor subtypes share many common
properties. They are G-protein-coupled receptors with seven transmembrane
domains of the aminebinding subfamily. All three subtypes are coupled to
the Gi/o signalling system, inhibiting the activity of adenylate cyclase,
the opening of voltage-gated Ca2+ channels and the opening of
K.sup.+ channels. The three receptors are encoded by distinct genes
(Bylund, D. B.; et al. Pharmacol. Rev. 1994, 46, 121-136 and Hieble, J.
P. et al. Pharmacol. Commun. 1995, 6, 91-97), localized to different
chromosomes; in humans the gene for α2A is found on chromosome
10, the α2B-gene on chromosome 2 and the α2C-gene
on chromosome 4. The subtypes are well conserved across mammalian
species. In rats and mice, however, there is a single amino acid
substitution which decreases the affinity of the rodent
α2A-adrenoceptor for the classical α2-antagonists,
yohimbine and rauwolscine. The general consensus is that this so-called
α2D-adrenoceptor subtype represents the rodent homologue of
the human α2A-subtype.

[0005]The α2-adrenoceptor subtypes are differentially
distributed in cells and tissues, clearly endowing the receptors with
different physiological functions and pharmacological activity profiles.
Different regulatory regions in the receptor genes and different protein
structures also confer different regulatory properties on the three
receptors, both with regard to receptor synthesis and post-translational
events.

[0006]2-Adrenergic receptors were initially characterized as presynaptic
receptors that serve as parts of a negative feedback loop to regulate the
release of norepinephrine. Soon it was shown that
α2-adrenoceptors are not restricted to presynaptic locations
but also have postsynaptic functions. The α2A-adrenoceptor is
the major inhibitory presynaptic receptor (autoreceptor) regulating
release of norepinephrine from sympathetic neurons as part of a feedback
loop. The α2C-adrenoceptor turned out to function as an
additional presynaptic regulator in all central and peripheral nervous
tissues investigated. However, the relative contributions of
α2A and α2C-receptors differed between central and
peripheral nerves, with the α2C-subtype being more prominent
in sympathetic nerve endings than in central adrenergic neurons (Philipp,
M. et al. Am. J. Physiol. Regul. Integr. Comput. Physiol. 2002, 283,
R287-R295 and Kable, J. W. et al. J. Pharmacol. Exp. Ther. 2000, 293,
1-7). The α2C-adrenoceptor is particularly suited to control
neurotransmitter release at low action potential frequencies. In
contrast, the α2A-adrenoceptor seems to operate primarily at
high stimulation frequencies in sympathetic nerves and may thus be
responsible for controlling norepinephrine release during maximal
sympathetic activation (Bucheler, M. M. et al. Neuroscience 2002, 109,
819-826). α2B-Adrenoceptors are located on postsynaptic cells
to mediate the effects of catecholamines released from sympathetic
nerves, e.g., vasoconstriction. α2-Adrenergic receptors not
only inhibit release of their own neurotransmitters but can also regulate
the exocytosis of a number of other neurotransmitters in the central and
peripheral nervous system. In the brain, α2A- and
α2C-adrenoceptors can inhibit dopamine release in basal
ganglia as well as serotonin secretion in mouse hippocampal or brain
cortex slices. In contrast, the inhibitory effect of
α2-adrenoceptor agonists on gastrointestinal motility was
mediated solely by the α2A-subtype. Part of the functional
differences between α2A- and α2C-receptors may be
explained by their distinct subcellular localization patterns. When
expressed in rat fibroblasts, α2A- and
α2B-adrenoceptors are targeted to the plasma membrane. On
stimulation with agonist, only α2B-adrenoceptors are
reversibly internalized into endosomes. α2C-Adrenoceptors are
primarily localized in an intracellular membrane compartment, from where
they can be translocated to the cell surface after exposure to cold
temperature (see a.o. Docherty J. R. et. al. Eur. J. Pharmacol. 1998,
361, 1-15).

[0007]The establishment of genetically engineered mice lacking or
overexpressing α2-adrenoceptor subtypes has yielded important
information for understanding the subtype specific functions (MacDonald,
E. et al. Trends Pharmacol. Sci. 1997, 18, 211-219). The examination of
the phenotype of these strains of mice demonstrated that the
α2A-subtype is responsible for inhibition of neurotransmitter
release from central and peripheral sympathetic nerves and for most of
the centrally mediated effects of α2-agonists. The
α2B subtype is primarily responsible for the initial
peripheral hypertensive responses evoked by the α2-agonists
and takes part in the hypertension induced by salt (Link et al. Science
1996, 273, 803-805 and Makaritsis, K. P. et al. Hypertension 1999, 33,
14-17).

[0008]Clarification of the physiological role of the α2C
subtype proved more difficult. Despite a rather wide distribution in the
CNS, its role did not appear critical in the mediation of the
cardiovascular effects of nonselective α2-agonists. Its
participation has been suggested in the hypothermia induced by
dexmedetomidine and in the hyperlocomotion induced by D-amphetamine
(Rohrer, D. K. et al. Annu. Rev. Pharmacol Toxicol. 1998, 38, 351-373).
Another potentially important response mediated by the
α2C-adrenoceptor is constriction of cutaneous arteries,
leading to a reduction in cutaneous blood flow (Chotani, M. A. et al. Am.
J. Physiol. Heart Circ. Physiol. 2004, 286, 59-67). Recent studies
carried out on double knockout mice have suggested that
α2C-adrenoceptor is also expressed at the presynaptic level
where, together with α2A, it actively participates in the
control of neurotransmitter release. While α2A-adrenoceptor is
particularly efficient at high stimulation frequencies,
α2C-adrenoceptor acts rather at low stimulation frequencies.
Moreover, it has been suggested that α2C subtype participates
in the modulation of motor behavior and the memory processes (Bjorklund,
M. et al. Neuroscience 1999, 88, 1187-1198 and Tanila, H. et al. Eur. J.
Neurosci. 1999, 11, 599-603). Other central effects triggered by this
subtype include also the startle reflex and aggression response to stress
and locomotion (Sallinen, J. et al. J. Neurosci. 1998, 18, 3035-3042 and
Sallinen. J. et al. Neuroscience 1998, 86, 959-965). Last, it was
recently pointed out that the α2C-adrenoceptor might
contribute to α2-agonist-mediated spinal analgesia and
adrenergic-opioid synergy (Fairbanks, C. A. et al. J. Pharm. Exp. Ther.
2002, 300, 282-290).

[0009]Because of their widespread distribution in the central nervous
system, α2-receptors affect a number of behavioral functions.
The effect of altered α2C-adrenergic receptor expression has
been evaluated in several different behavioral paradigms (Kable J. W. et
al., Journal of Pharmacology and Experimental Therapeutics, 2000, 293
(1): 1-7), proving that α2C-adrenergic antagonists may have
therapeutic value in the treatment of stress-related psychiatric
disorders. In each of the behavioral paradigms, it is unclear whether the
α2C-subtype plays some direct role in mediating behavior or
whether altered α2C-receptor expression produces effects
because of altered metabolism or downstream modulation of other
neurotransmitter systems. Interestingly,
α2C-receptor-deficient mice had enhanced startle responses,
diminished pre-pulse inhibition, and shortened attack latency in the
isolation aggression test. Thus drugs acting via the
α2C-adrenoceptor may have therapeutic value in disorders
associated with enhanced startle responses and sensorimotor gating
deficits, such as schizophrenia, attention deficit disorder,
posttraumatic stress disorder, and drug withdrawal. In addition to the
α2C-subtype, the α2A-adrenoceptor has an important.

[0010]With more and more studies of the α2-adrenoceptor
physiology in gene-targeted mice being published, the situation becomes
more complicated than initially anticipated. Indeed, only a few
biological functions of α2-receptors were found to be mediated
by one single α2-adrenergic receptor subtype. For other
α2-receptor-mediated functions, two different strategies seem
to have emerged to regulate adrenergic signal transduction: some
biological functions are controlled by two counteracting
α2-receptor subtypes, and some require two receptor subtypes
with similar but complementary effects. Because the
α2A-subtype mediates most of the classical effects of
α2-adrenergic agonists, it is doubtful that an
α2A-selective agonist would have a substantially better
clinical profile than the currently available agents. Drugs acting at
α2B- or α2C-adrenergic receptors are likely to have
fewer of the classical α2-adrenergic side effects than
α2A-specific agents. It would appear likely that
α2C-selective agents may be useful in at least some nervous
system disorders, in particular central nervous system disorders.

BACKGROUND PRIOR ART

[0011]Analysis of the pipeline databases to date indicate that there are
several adrenergic α2-antagonists in the market, by companies
including Akzo Nobel (Organon), Novartis, Pfizer, and Schering AG. None
of those compounds are selective for any of the three
α2-adrenoceptors. These compounds are indicated mainly for
depression, hypertensive disorders and dyskinesias associated with
Parkinson's disease. Companies with α2-adrenoceptor
antagonists in clinical development include Britannia Pharmaceuticals,
IVAX, Juvantia Pharmaceuticals, MAP Pharmaceuticals, Novartis, Novo
Nordisk, Organon, Pierre Fabre, and Sanofi-Aventis.

[0012]Regarding the development of selective α2C-adrenoceptor
antagonists to date, OPC-28326 is the only compound in clinical
development (in Phase 2 by Otsuka Pharmaceuticals for hypertensive
disorders and peripheral vascular disease). The rest of the
α2C antagonists are in preclinical development by Oy Juvantia
Pharma Ltd (JP 1514 and JP 1302, published in WO 01/64645 and WO
04/067513) and by Novartis AG (NVP-ABE651 and NVP-ABE697, published in WO
01/55132 and J. Label Compd. Radiopharm 2002, 45, 1180), indicated mainly
for depression and schizophrenia. In addition, several compounds are
listed at the very early stages of development (biological testing) by
Juvantia and Kyowa Hakko, for depression and Parkinson's disease.

DESCRIPTION OF THE INVENTION

[0013]It is the object of the present invention to provide compounds with
a binding affinity towards α2-adrenoceptor receptors, in
particular towards α2C-adrenoceptor receptors, in particular
as an antagonist.

[0014]This goal was achieved by a novel substituted pyrazinone derivative
according to the general Formula (I)

a pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof, an N-oxide form thereof or a
quaternary ammonium salt thereof, wherein: [0015]V is a naphthyl-radical,
wherein one CH-unit in the napthyl-moiety may optionally be replaced by a
N-atom; [0016]Y is a bivalent radical of Formula (II)

[0016]wherein [0017]A is a nitrogen or a carbon-atom [0018]m is an integer
equal to zero, 1 or 2 [0019]R4 is selected from the group of
hydrogen; alkyl and phenylcarboxylalkyl; [0020]R5 is selected from
the group of hydrogen and halo; [0021]X1, X2 are each,
independently from each other, a covalent bond, a saturated or an
unsaturated (C1-8)-hydrocarbon radical, wherein one or more bivalent
--CH2-units and/or one or more monovalent CH3-units may
optionally be replaced by a respective bivalent or monovalent
phenyl-unit; and wherein one or more hydrogen atoms may be replaced by a
radical selected from the group of oxo; (C1-3)alkyloxy; halo; cyano;
nitro; formyl; hydroxy; amino; trifluoromethyl mono- and
di((C1-3)alkyl)amino; carboxy; and thio; [0022]p, q are each,
independently from each other, an integer equal to 1 or 2; [0023]Q1,
Q2 are each, independently from each other, a radical selected from
the group of hydrogen; --NR1R2; Pir; --OR3 and Het;
wherein two radicals --OR3 may be taken together to form a bivalent
radical --O--(CH2)r--O-- wherein r is an integer equal to 1, 2
or 3; [0024]R1 and R2 are each, independently from each other,
a radical selected from the group of hydrogen; alkyl; alkenyl; alkynyl;
aryl; arylalkyl; alkylcarbonyl; alkenylcarbonyl; alkyloxy; alkyloxyalkyl;
alkyloxycarbonyl; alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; alkylsulfonyl; arylcarbonyl; aryloxyalkyl
arylalkylcarbonyl; arylsulfonyl; Het; Het-alkyl; Het-alkylcarbonyl
Het-carbonyl; Het-carbonylalkyl; alkyl-NRaRb;
carbonyl-NRaRb; carbonylalkyl-NRaRb;
alkylcarbonyl-NRaRb; and alkylcarbonylalkyl-NRaRb;
wherein Ra and Rb are each independently selected from the
group of hydrogen, alkyl, alkylcarbonyl, alkyloxyalkyl,
alkyloxycarbonylalkyl, aryl, arylalkyl, Het and alkyl-NRcRd,
wherein Rc and Rd are each independently from each other
hydrogen or alkyl; [0025]Pir is a radical containing at least one N, by
which it is attached to the X-radical, selected from the group of
pyrrolidinyl; imidazolidinyl; pyrazolidinyl; piperidinyl; piperazinyl;
pyrrolyl; pyrrolinyl; imidazolinyl; pyrrazolinyl; pyrrolyl; imidazolyl;
pyrazolyl; triazolyl; azepyl; diazepyl; morpholinyl; thiomorpholinyl;
indolyl; isoindolyl; indolinyl; indazolyl; benzimidazolyl; and
1,2,3,4-tetrahydro-isoquinolinyl; wherein each Pir-radical is optionally
substituted by 1, 2 or 3 radicals selected from the group of hydroxy;
halo; oxo; (C1-3)alkyl; trifluoromethyl; phenyl; benzyl
pyrrolidinyl; and pyridinyloxy; [0026]R3 is a radical selected from
the group of hydrogen; alkyl; aryl arylalkyl; Het; and Het-alkyl;
[0027]Het is a heterocyclic radical selected from the group of
pyrrolidinyl imidazolidinyl; pyrazolidinyl; piperidinyl; piperazinyl;
pyrrolyl; pyrrolinyl; imidazolinyl; pyrrazolinyl; pyrrolyl; imidazolyl;
pyrazolyl triazolyl; pyridinyl; pyridazinyl; pyrimidinyl; pyrazinyl;
triazinyl azepyl; diazepyl; morpholinyl; thiomorpholinyl; indolyl;
isoindolyl; indolinyl; indazolyl; benzimidazolyl
1,2,3,4-tetrahydro-isoquinolinyl; furyl; thienyl; oxazolyl; isoxazolyl;
thiazolyl; thiadiazolyl; isothiazolyl; dioxolyl; dithianyl;
tetrahydrofuryl; tetrahydropyranyl; quinolinyl; isoquinolinyl;
quinoxalinyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl;
benzisothiazolyl; benzofuranyl; benzothienyl; benzopiperidinyl;
chromenyl; and imidazo[1,2-a]pyridinyl; wherein each Het-radical is
optionally substituted by one or more radicals selected from the group of
halo; oxo; (C1-3)alkyl; (C1-3)alkylcarbonyl;
(C1-3)alkenylthio; imidazolyl-(C1-3)alkyl; and
(C1-3)alkyloxycarbonyl; [0028]aryl is naphthalenyl or phenyl, each
optionally substituted with 1, 2 or 3 substituents, each independently
from each other, selected from the group of oxo; (C1-3)alkyl;
(C1-3)alkyloxy; halo; cyano; nitro; formyl; hydroxy; amino;
trifluoromethyl; mono- and di((C1-3)alkyl)amino; carboxy; and thio;
[0029]alkyl is a straight or branched saturated hydrocarbon radical
having from 1 to 8 carbon atoms; or is a cyclic saturated hydrocarbon
radical having from 3 to 7 carbon atoms; or is a cyclic saturated
hydrocarbon radical having from 3 to 7 carbon atoms attached to a
straight or branched saturated hydrocarbon radical having from 1 to 8
carbon atoms; wherein each radical is optionally substituted on one or
more carbon atoms with one or more radicals selected from the group of
oxo; (C1-3)alkyloxy; halo; cyano; nitro; formyl; hydroxy; amino;
carboxy; and thio; [0030]alkenyl is an alkyl radical as defined above,
further having one or more double bonds; [0031]alkynyl is an alkyl
radical as defined above, further having one or more triple bonds; and
[0032]arylalkyl is an alkyl radical as defined above, further having one
or more CH3-groups replaced by phenyl.

[0033]The invention also relates to a pharmaceutical composition
comprising a pharmaceutically acceptable carrier or diluent and, as
active ingredient, a therapeutically effective amount of a compound
according to the invention, in particular a compound according to Formula
(I), a pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof, an N-oxide form thereof or a
quaternary ammonium salt thereof.

[0034]The invention also relates to the use of a compound according to the
invention for the preparation of a medicament for the prevention and/or
treatment of a disorder or disease responsive to antagonism of the
α2-adrenergic receptor, in particular to antagonism of the
α2C-adrenergic receptor.

[0035]In particular, the invention relates to the use of a compound
according to the invention for the preparation of a medicament for the
prevention and/or treatment of central nervous system disorders, mood
disorders, anxiety disorders, stress-related disorders associated with
depression and/or anxiety, cognitive disorders, personality disorders,
schizoaffective disorders, Parkinson's disease, dementia of the
Alzheimer's type, chronic pain conditions, neurodegenerative diseases,
addiction disorders, mood disorders and sexual dysfunction.

[0036]The compounds according to the invention may also be suitable as
add-on treatment and/or prophylaxis in the above listed diseases in
combination with antidepressants, anxiolytics and/or antipsychotics which
are currently available or in development or which will become available
in the future, to improve efficacy and/or onset of action. This is
evaluated in rodent models in which antidepressants, anxiolytics and/or
antipsychotics are shown to be active. For example, compounds are
evaluated in combination with antidepressants, anxiolytics and/or
antipsychotics for attenuation of stress-induced hyperthermia.

[0037]The invention therefore also relates to the use of the compounds
according to the invention for use as an add-on treatment with one or
more other compounds selected from the group of antidepressants,
anxiolytics and antipsychotics, to a pharmaceutical composition
comprising the compounds according to the invention and one or more other
compounds selected from the group of antidepressants, anxiolytics and
antipsychotics, as well as to a process for the preparation of such
pharmaceutical compositions and to the use of such a composition for the
manufacture of a medicament, in particular to improve efficacy and/or
onset of action in the treatment of depression and/or anxiety.

DETAILED DESCRIPTION OF THE INVENTION

[0038]In one embodiment, the invention relates to a compound according to
general Formula (I), a pharmaceutically acceptable acid or base addition
salt thereof, a stereochemically isomeric form thereof, an N-oxide form
thereof or a quaternary ammonium salt thereof, wherein V is selected from
the group of radicals (z-1), (z-2), (z-3), (z-4), (z-5) and (z-6).

[0039]More particularly, V is selected from the group of radicals (z-1),
(z-2), (z-3), (z-5), and (z-6).

[0040]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein A is
a carbon atom, m is zero and R4 is hydrogen.

[0041]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein the
moiety --CH2--Y-- is attached to V by the atom, denoted by "a".

[0042]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein
R5 is chloro.

[0043]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein each
of X1 and X2, independently from each other, are selected from
the group of a covalent bond; --CH2--; --CH2CH2--;
--CH2CH2CH2--; --CH2CH2CH2CH2--;
--CH2CH═CHCH2--; --CH2C≡CCH2--;
--CH(CH3)CH(CH3)--; --C(═O)CH2--;
--C(═O)CH2CH2--; --C(═O)CH2CH2CH2--;
--CH2C(═O)--; --CH2CH2C(═O)--;
--CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--;
--CH2CH2C(═O)CH2--; --C6H4--;
--CH2C6H4--; --CH2CH2C6H4--;
--CH2CH2CH2C6H4--; --C6H4CH2--;
--C6H4CH2CH2--;
--C6H4CH2CH2CH2--;
--CH2C6H4CH2--;
--CH2CH2C6H4CH2CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H4--.

[0044]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein each
of X1 and X2, independently from each other, are selected from
the group of a covalent bond; --CH2--; --CH2CH2--;
--CH2CH2CH2--; --CH2CH2CH2CH2--;
--CH2CH═CHCH2--; --CH2C≡CCH2--;
--CH2C(═O)--; --CH2CH2C(═O)--;
--CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--; --C6H4--;
--CH2C6H4--; --CH2CH2CH2C6H4--;
--C6H4CH2--; --CH2C6H4CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H4--.

[0045]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein one
or more hydrogen atoms in each of X1 and X2 are optionally
replaced by a radical selected from the group of oxo;
(C1-3)alkyloxy; halo; cyano; nitro; and formyl.

[0046]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein
X1 is a covalent bond, Q1 is hydrogen and p is 1.

[0047]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein
R1 and R2 are each, independently from each other, a radical
selected from the group of hydrogen; alkyl; alkenyl alkynyl; aryl;
arylalkyl; alkylcarbonyl; alkenylcarbonyl; alkyloxyalkyl
alkyloxycarbonyl; alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; arylcarbonyl; aryloxyalkyl;
arylalkylcarbonyl; Het-alkyl; Het-alkylcarbonyl; Het-carbonyl;
Het-carbonylalkyl; alkyl-NRaRb; carbonyl-N RaRb;
carbonylalkyl-NRaRb alkylcarbonyl-NRaRb; and
alkylcarbonylalkyl-NRaRb; wherein each of Ra and Rb
independently are selected from the group of hydrogen, alkyl,
alkylcarbonyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, arylalkyl, Het
and alkyl-NRcRd, wherein Rc and Rd are each
independently from each other hydrogen or alkyl.

[0048]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein Pir
is a radical containing at least one N, by which it is attached to the
X-radical, selected from the group of pyrrolidinyl; piperidinyl;
piperazinyl; imidazolyl; morpholinyl; isoindolyl; wherein each
Pir-radical is optionally substituted by 1, 2 or 3 radicals selected from
the group of hydroxy; halo; oxo; (C1-3)alkyl; trifluoromethyl;
phenyl; benzyl; pyrrolidinyl; and pyridinyloxy. With the X-radical is
meant either or both of the X1-radical and the X2-radical.

[0049]More particularly, the invention relates to a compound according to
general Formula (I), a pharmaceutically acceptable acid or base addition
salt thereof, a stereochemically isomeric form thereof, an N-oxide form
thereof or a quaternary ammonium salt thereof, wherein Het is a
heterocyclic radical selected from the group of piperidinyl; piperazinyl;
triazolyl; pyridinyl; pyrimidinyl; morpholinyl; indolyl; furyl; thienyl;
isoxazolyl; thiazolyl; tetrahydrofuryl; tetrahydropyranyl; quinolinyl;
isoquinolinyl; benzofuranyl; benzothienyl; and benzopiperidinyl; wherein
each Het-radical is optionally substituted by one or more radicals
selected from the group of oxo; (C1-3)alkyl;
(C1-3)alkylcarbonyl and imidazolyl-(C1-3)alkyl.

[0050]Most particularly, the invention relates to a compound according to
general Formula (I), a pharmaceutically acceptable acid or base addition
salt thereof, a stereochemically isomeric form thereof, an N-oxide form
thereof or a quaternary ammonium salt thereof, wherein aryl is phenyl,
optionally substituted with 1, 2 or 3 substituents, each independently
from each other, selected from the group of (C1-3)alkyl; halo; and
trifluoromethyl.

[0051]In another embodiment, the invention relates to a compound according
to general Formula (I), a pharmaceutically acceptable acid or base
addition salt thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, wherein
[0052]V is selected from the group of radicals (z-1), (z-2), (z-3), (z-5)
and (z-6); wherein the moiety --CH2--Y-- is attached to V by the
atom, denoted by "a"; [0053]Y is a bivalent radical of Formula (II)
wherein A is a nitrogen or a carbon-atom; m is an integer equal to zero
or 2; and R4 is selected from the group of hydrogen; alkyl and
phenylcarboxylalkyl [0054]R5 is selected from the group of hydrogen
and halo; [0055]X1, X2 are each, independently from each other,
are selected from the group of a covalent bond; --CH2--;
--CH2CH2--; --CH2CH2CH2--;
--CH2CH2CH2CH2--; --CH2CH═CHCH2--;
--CH2C≡CCH2--; --CH2C(═O)--;
--CH2CH2C(═O)--; --CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--; --C6H4--;
--CH2C6H4--; --CH2CH2CH2C6H4--;
--C6H4CH2--; --CH2C6H4CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H4--; and wherein one or more
hydrogen atoms may be replaced by a radical selected from the group of
oxo; (C1-3)alkyloxy; halo; cyano; nitro; and formyl; [0056]p, q are
each, independently from each other, an integer equal to 1 or 2;
[0057]Q1, Q2 are each, independently from each other, a radical
selected from the group of hydrogen; --NR1R2; Pir; --OR3
and Het; wherein two radicals --OR3 may be taken together to form a
bivalent radical --O--(CH2)r--O-- wherein r is an integer equal
to 1, 2 or 3; [0058]R1 and R2 are each, independently from each
other, a radical selected from the group of hydrogen; alkyl; alkenyl;
alkynyl; aryl; arylalkyl alkylcarbonyl; alkenylcarbonyl; alkyloxyalkyl;
alkyloxycarbonyl alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; arylcarbonyl; aryloxyalkyl;
arylalkylcarbonyl Het-alkyl; Het-alkylcarbonyl; Het-carbonyl;
Het-carbonylalkyl alkyl-NRaRb; carbonyl-NaRb;
carbonylalkyl-NRaRb; alkylcarbonyl-NRaRb; and
alkylcarbonylalkyl-NRaRb; wherein Ra and Rb are each
independently selected from the group of hydrogen, alkyl, alkylcarbonyl,
alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, arylalkyl, Het and
alkyl-NRcRd, wherein Rc and Rd are each independently
from each other hydrogen or alkyl; [0059]Pir is a radical containing at
least one N, by which it is attached to the X-radical, selected from the
group of pyrrolidinyl; piperidinyl; piperazinyl; imidazolyl; morpholinyl;
isoindolyl; wherein each Pir-radical is optionally substituted by 1, 2 or
3 radicals selected from the group of hydroxy; halo; oxo;
(C1-3)alkyl; trifluoromethyl; phenyl; benzyl; pyrrolidinyl; and
pyridinyloxy; [0060]R3 is a radical selected from the group of
hydrogen; alkyl; aryl; arylalkyl; Het; and Het-alkyl; [0061]Het is a
heterocyclic radical selected from the group of piperidinyl; piperazinyl;
triazolyl; pyridinyl; pyrimidinyl; morpholinyl; indolyl; furyl; thienyl;
isoxazolyl; thiazolyl; tetrahydrofuryl; tetrahydropyranyl; quinolinyl;
isoquinolinyl; benzofuranyl; benzothienyl; and benzopiperidinyl; wherein
each Het-radical is optionally substituted by one or more radicals
selected from the group of oxo; (C1-3)alkyl;
(C1-3)alkylcarbonyl; and imidazolyl-(C1-3)alkyl; [0062]aryl is
phenyl, optionally substituted with 1, 2 or 3 substituents, each
independently from each other, selected from the group of
(C1-3)alkyl; halo; and trifluoromethyl; [0063]alkyl is a straight or
branched saturated hydrocarbon radical having from 1 to 8 carbon atoms;
or is a cyclic saturated hydrocarbon radical having from 3 to 7 carbon
atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 7
carbon atoms attached to a straight or branched saturated hydrocarbon
radical having from 1 to 8 carbon atoms; wherein each radical is
optionally substituted on one or more carbon atoms with one or more
radicals selected from the group of oxo; (C1-3)alkyloxy; halo;
cyano; nitro; formyl; hydroxy; amino; carboxy; and thio; [0064]alkenyl is
an alkyl radical as defined above, further having one or more double
bonds; [0065]alkynyl is an alkyl radical as defined above, further having
one or more triple bonds; and [0066]arylalkyl is an alkyl radical as
defined above, further having one or more CH3-groups replaced by
phenyl.

[0067]In the framework of this application, alkyl is a straight or
branched saturated hydrocarbon radical having from 1 to 8 carbon atoms;
or is a cyclic saturated hydrocarbon radical having from 3 to 7 carbon
atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 7
carbon atoms attached to a straight or branched saturated hydrocarbon
radical having from 1 to 8 carbon atoms; wherein each radical is
optionally substituted on one or more carbon atoms with one or more
radicals selected from the group of oxo; (C1-3)alkyloxy; halo;
cyano; nitro; formyl; hydroxy; amino; carboxy; and thio. Particularly,
alkyl is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,
hexyl, pentyl, octyl, cyclopropyl, cyclopentyl, cyclohexyl,
cyclohexylmethyl and cyclohexylethyl.

[0068]Finally, the invention relates to a compound according to general
Formula (I), a pharmaceutically acceptable acid or base addition salt
thereof, a stereochemically isomeric form thereof, an N-oxide form
thereof or a quaternary ammonium salt thereof, wherein one or more the
following restrictions, alone or in combination, apply: [0069]V is
selected from the group of radicals (z-1), (z-2), (z-3), (z-4), (z-5) and
(z-6); or [0070]V is selected from the group of radicals (z-1), (z-2),
(z-3), (z-5), and (z-6) [0071]A is a carbon atom, m is zero and R4
is hydrogen; [0072]the moiety --CH2--Y-- is attached to V by the
atom, denoted by "a" [0073]R5 is chloro; [0074]each of X1 and
X2, independently from each other, are selected from the group of a
covalent bond; --CH2--; --CH2CH2--;
--CH2CH2CH2--; --CH2CH2CH2CH2--;
--CH2CH═CHCH2--; --CH2C≡CCH2--;
--CH(CH3)CH(CH3)--; --C(═O)CH2--;
--C(═O)CH2CH2--; --C(═O)CH2CH2CH2--;
--CH2C(═O)--; --CH2CH2C(═O)--;
--CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--;
--CH2CH2C(═O)CH2--; --C6H4--;
--CH2C6H4--; --CH2CH2C6H4--;
--CH2CH2CH2C6H4--; --C6H4CH2--;
--C6H4CH2CH2--;
--C6H4CH2CH2CH2--;
--CH2C6H4CH2--;
--CH2CH2C6H4CH2CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H4--; or [0075]each of X1 and
X2, independently from each other, are selected from the group of a
covalent bond; --CH2--; --CH2CH2--;
--CH2CH2CH2--; --CH2CH2CH2CH2--;
--CH2CH═CHCH2--; --CH2C≡CCH2--;
--CH2C(═O)--; --CH2CH2C(═O)--;
--CH2CH2CH2C(═O)--;
--CH2CH2CH2CH2C(═O)--; --C6H4--;
--CH2C6H4--; --CH2CH2CH2C6H4--;
--C6H4CH2--; --CH2C6H4CH2--;
--C6H4C(═O)--; --C6H4CH2C(═O)--;
--C6H4CH2CH2C(═O)--; and
--CH2CH2C(═O)C6H4--; [0076]one or more hydrogen
atoms in each of X1 and X2 are optionally replaced by a radical
selected from the group of oxo; (C1-3)alkyloxy; halo; cyano; nitro;
and formyl; [0077]X1 is a covalent bond, Q1 is hydrogen and p
is 1; [0078]R1 and R2 are each, independently from each other,
a radical selected from the group of hydrogen; alkyl; alkenyl; alkynyl;
aryl; arylalkyl; alkylcarbonyl; alkenylcarbonyl; alkyloxyalkyl;
alkyloxycarbonyl; alkyloxyalkylcarbonyl; alkyloxycarbonylalkyl;
alkyloxycarbonylalkylcarbonyl; arylcarbonyl; aryloxyalkyl;
arylalkylcarbonyl; Het-alkyl; Het-alkylcarbonyl; Het-carbonyl;
Het-carbonylalkyl; alkyl-NRaRb; carbonyl-NRaRb;
carbonylalkyl-NaRb alkylylcarbonyl-NRaRb; and
alkylcarbonylalkyl-NRaRb; wherein each of Ra and Rb
independently are selected from the group of hydrogen, alkyl,
alkylcarbonyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, arylalkyl, Het
and alkyl-NRcRd, wherein Rc and Rd are each
independently from each other hydrogen or alkyl; [0079]Pir is a radical
containing at least one N, by which it is attached to the X-radical,
selected from the group of pyrrolidinyl; piperidinyl; piperazinyl;
imidazolyl; morpholinyl; isoindolyl; wherein each Pir-radical is
optionally substituted by 1, 2 or 3 radicals selected from the group of
hydroxy; halo; oxo; (C1-3)alkyl; trifluoromethyl; phenyl; benzyl;
pyrrolidinyl; and pyridinyloxy; [0080]Het is a heterocyclic radical
selected from the group of piperidinyl; piperazinyl; triazolyl;
pyridinyl; pyrimidinyl; morpholinyl; indolyl; furyl; thienyl; isoxazolyl;
thiazolyl; tetrahydrofuryl; tetrahydropyranyl; quinolinyl; isoquinolinyl;
benzofuranyl; benzothienyl; and benzopiperidinyl; wherein each
Het-radical is optionally substituted by one or more radicals selected
from the group of oxo; (C1-3)alkyl; (C1-3)alkylcarbonyl; and
imidazolyl-(C1-3)alkyl; [0081]aryl is phenyl, optionally substituted
with 1, 2 or 3 substituents, each independently from each other, selected
from the group of (C1-3)alkyl; halo; and trifluoromethyl.

[0082]In the framework of this application, alkenyl is an alkyl radical as
defined above having one or more double bonds. Particularly, alkenyl is
ethenyl, propenyl and butynyl.

[0083]In the framework of this application, alkynyl is an alkyl radical as
defined above having one or more triple bonds. Particularly, alkynyl is
ethynyl and propynyl.

[0084]In the framework of this application, arylalkyl is an alkyl radical
as defined above, having one or more --CH3-radicals replaced by
phenyl-radical. Examples of such radicals are benzyl, diphenylmethyl and
1,1-diphenylethyl.

[0085]In the framework of this application, halo is a substituent selected
from the group of fluoro, chloro, bromo and iodo and haloalkyl is a
straight or branched saturated hydrocarbon radical having from 1 to 6
carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 7
carbon atoms, wherein one or more carbon atoms is substituted with one or
more halo atoms. Particularly, halo is bromo, fluoro or chloro and
particularly, haloalkyl is trifluoromethyl.

[0086]In the framework of this application, with "compounds according to
the invention" is meant a compound according to the general Formula (I),
a pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof, an N-oxide form thereof or a
quaternary ammonium salt thereof.

[0090]Conversely, said salts forms can be converted into the free forms by
treatment with an appropriate acid.

[0091]Quaternary ammonium salts of compounds according to Formula (I)
defines said compounds which are able to form by a reaction between a
basic nitrogen of a compound according to Formula (I) and an appropriate
quaternizing agent, such as, for example, an optionally substituted
alkylhalide, arylhalide or arylalkylhalide, in particular methyliodide
and benzyliodide. Other reactants with good leaving groups may also be
used, such as, for example, alkyl trifluoromethanesulfonates, alkyl
methanesulfonates and alkyl p-toluenesulfonates. A quaternary ammonium
salt has a positively charged nitrogen. Pharmaceutically acceptable
counterions include chloro, bromo, iodo, trifluoroacetate and acetate
ions.

[0092]The term addition salt as used in the framework of this application
also comprises the solvates that the compounds according to Formula (I)
as well as the salts thereof, are able to form. Such solvates are, for
example, hydrates and alcoholates.

[0093]The N-oxide forms of the compounds according to Formula (I) are
meant to comprise those compounds of Formula (I) wherein one or several
nitrogen atoms are oxidized to the so-called N-oxide, particularly those
N-oxides wherein one or more tertiary nitrogens (e.g. of the piperazinyl
or piperidinyl radical) are N-oxidized. Such N-oxides can easily be
obtained by a skilled person without any inventive skills and they are
obvious alternatives for the compounds according to Formula (I) since
these compounds are metabolites, which are formed by oxidation in the
human body upon uptake. As is generally known, oxidation is normally the
first step involved in drug metabolism (Textbook of Organic Medicinal and
Pharmaceutical Chemistry, 1977, pages 70-75). As is also generally known,
the metabolite form of a compound can also be administered to a human
instead of the compound per se, with much the same effects.

[0095]The term "stereochemically isomeric forms" as used hereinbefore
defines all the possible isomeric forms that the compounds of Formula (I)
may possess. Unless otherwise mentioned or indicated, the chemical
designation of compounds denotes the mixture of all possible
stereochemically isomeric forms, said mixtures containing all
diastereomers and enantiomers of the basic molecular structure. More in
particular, stereogenic centers may have the R- or S-configuration;
substituents on bivalent cyclic (partially) saturated radicals may have
either the cis- or trans-configuration. Compounds encompassing double
bonds can have an E or Z-stereochemistry at said double bond.
Stereochemically isomeric forms of the compounds of Formula (I) are
obviously intended to be embraced within the scope of this invention.

[0096]Following CAS nomenclature conventions, when two stereogenic centers
of known absolute configuration are present in a molecule, an R or S
descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the
lowest-numbered chiral center, the reference center. The configuration of
the second stereogenic center is indicated using relative descriptors
[R*,R*] or [R*,S*], where R* is always specified as the reference center
and [R*,R*] indicates centers with the same chirality and [R*,S*]
indicates centers of unlike chirality. For example, if the
lowest-numbered chiral center in the molecule has an S configuration and
the second center is R, the stereo descriptor would be specified as
S--[R*,S*]. If "α" and "β" are used: the position of the
highest priority substituent on the asymmetric carbon atom in the ring
system having the lowest ring number, is arbitrarily always in the
"α" position of the mean plane determined by the ring system. The
position of the highest priority substituent on the other asymmetric
carbon atom in the ring system (hydrogen atom in compounds according to
Formula (I)) relative to the position of the highest priority substituent
on the reference atom is denominated "α", if it is on the same side
of the mean plane determined by the ring system, or "β", if it is on
the other side of the mean plane determined by the ring system.

[0097]The invention also comprises derivative compounds (usually called
"pro-drugs") of the pharmacologically-active compounds according to the
invention, which are degraded in vivo to yield the compounds according to
the invention. Pro-drugs are usually (but not always) of lower potency at
the target receptor than the compounds to which they are degraded.
Pro-drugs are particularly useful when the desired compound has chemical
or physical properties that make its administration difficult or
inefficient. For example, the desired compound may be only poorly
soluble, it may be poorly transported across the mucosal epithelium, or
it may have an undesirably short plasma half-life. Further discussion on
pro-drugs may be found in Stella, V. J. et al., "Prodrugs", Drug Delivery
Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.

[0098]Pro-drugs forms of the pharmacologically-active compounds according
to the invention will generally be compounds according to Formula (I),
the pharmaceutically acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof and the N-oxide form thereof,
having an acid group which is esterified or amidated. Included in such
esterified acid groups are groups of the formula --COORx, where
Rx is a C1-6alkyl, phenyl, benzyl or one of the following
groups:

[0099]Amidated groups include groups of the formula --CONRyRz,
wherein Ry is H, C1-6alkyl, phenyl or benzyl and Rz is
--OH, H, C1-6alkyl, phenyl or benzyl. Compounds according to the
invention having an amino group may be derivatised with a ketone or an
aldehyde such as formaldehyde to form a Mannich base. This base will
hydrolyze with first order kinetics in aqueous solution.

[0100]In the framework of this application, with "compounds according to
the invention" is meant a compound according to the general Formula (I),
the pharmaceutically acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the N-oxide form thereof and a
prodrug thereof.

[0101]In the framework of this application, an element, in particular when
mentioned in relation to a compound according to Formula (I), comprises
all isotopes and isotopic mixtures of this element, either naturally
occurring or synthetically produced, either with natural abundance or in
an isotopically enriched form. In particular, when hydrogen is mentioned,
it is understood to refer to 1H, 2H, 3H and mixtures
thereof; when carbon is mentioned, it is understood to refer to 11C,
12C, 13C, 14C and mixtures thereof; when nitrogen is
mentioned, it is understood to refer to 13N, 14N, 15N and
mixtures thereof; when oxygen is mentioned, it is understood to refer to
14O, 15O, 16O, 17O, 18O and mixtures thereof;
and when fluor is mentioned, it is understood to refer to 18F,
19F and mixtures thereof.

[0102]The compounds according to the invention therefore also comprise
compounds with one or more isotopes of one or more element, and mixtures
thereof, including radioactive compounds, also called radiolabelled
compounds, wherein one or more non-radioactive atoms has been replaced by
one of its radioactive isotopes. By the term "radiolabelled compound" is
meant any compound according to Formula (I), an N-oxide form, a
pharmaceutically acceptable addition salt or a stereochemically isomeric
form thereof, which contains at least one radioactive atom. For example,
compounds can be labelled with positron or with gamma emitting
radioactive isotopes. For radioligand-binding techniques (membrane
receptor assay), the 3H-atom or the 125I-atom is the atom of
choice to be replaced. For imaging, the most commonly used positron
emitting (PET) radioactive isotopes are 11C, 18F, 15O and
13N, all of which are accelerator produced and have half-lives of
20, 100, 2 and 10 minutes respectively. Since the half-lives of these
radioactive isotopes are so short, it is only feasible to use them at
institutions which have an accelerator on site for their production, thus
limiting their use. The most widely used of these are 18F,
99mTc, 201Tl and I231. The handling of these radioactive
isotopes, their production, isolation and incorporation in a molecule are
known to the skilled person.

[0103]In particular, the radioactive atom is selected from the group of
hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Particularly, the
radioactive atom is selected from the group of hydrogen, carbon and
halogen.

[0104]In particular, the radioactive isotope is selected from the group of
3H, 11C, 18F, 122I, 123I, 125I, 131I,
75Br, 76Br, 77Br and 82Br. Particularly, the
radioactive isotope is selected from the group of 3H, 11C and
18F.

Preparation

[0105]The compounds according to the invention can generally be prepared
by a succession of steps, each of which is known to the skilled person.
In particular, the pyrazinone derivatives can be prepared according to
one or more of the following preparation methods.

Preparation of the Intermediate Compound (1-4).

[0107]Alkylation reactions of the starting material 2,3-dichloropyrazine
(I-1) with aminoderivatives (I-2) (Scheme 1A) or (I-5) (Scheme 1B) may be
performed in an aprotic solvent, such as, for instance DMF or DMSO, in
the presence of an inorganic base, such as K2CO3,
Nα2CO3, NaOH or KOH, at a convenient temperature, either
by conventional heating or under microwave irradiation, for a period of
time to ensure the completion of the reaction, which may typically be
about 16 hours under conventional heating.

[0108]Hydrolysis reactions may be performed either in acidic inorganic
solvents, such as 10% HClaq, using a co-solvent such as THF, by
conventional heating or under microwave heating, for a period of time to
ensure the completion of the reaction, which may typically be about 16
hours under conventional heating, or under basic conditions, such as in
NaOHaq or in a DMSO solvent, for a period of time to ensure the
completion of the reaction, which may typically be about 0.5 hours under
microwave irradiation.

[0109]Hydrogenation may be performed in an alcoholic solvent, such as
MeOH, in the presence of AcOH and Pd/C, under conventional heating, for a
period of time to ensure the completion of the reaction, which may
typically be about 16 hours at about 50° C.

[0110]The reductive amination reaction may be performed in an aprotic
solvent such as 1,2-dichloroethane, in the presence of the reducing agent
such as triacetoxyborohydride, for a period of time to ensure the
completion of the reaction, which may typically be about 16 hours at room
temperature.

[0111]The intermediate compound (I-4) is the starting compound for the
compounds of the reaction schemes below. All variables are as defined in
Formula (I), unless otherwise specified.

Preparation of Final Compounds in which X2 is a Saturated or an
Unsaturated (C1-8)-Hydrocarbon Radical.

[0112]The W-radical in the compound W--X2-(Q2)q is a
leaving group, such as for instance Cl--, Br--, MeSO2O-- and
p-MePhSO2O--; X2 is a saturated or an unsaturated
(C1-8)-hydrocarbon radical and V, Y, Q2 and p are defined as in
Formula (I). The alkylation reaction may be performed in an aprotic
solvent, such as CH3CN, DMF or THF in the presence of an inorganic
base, such as K2CO3, Na2CO3, Cs2CO3, or an
organic base such as TBD, PS-TBD, at a convenient temperature, either
under conventional heating or microwave irradiation, for a period of time
to ensure the completion of the reaction, which may typically be about 20
minutes at about 120° C. under microwave irradiation.

Preparation of Final Compounds in which X2 is an Phenyl-Radical, or
X2 is a Covalent Bond and Q2 is a Heteroaryl-Radical.

[0113]The Hal-radical in Hal-X2-(Q2)p particularly
represents a Br- or I-radical or a suitable equivalent radical such as
B(OH)2. X2 is an optionally substituted phenyl; or X2 is a
covalent bond and Q2 is an optionally substituted heteroaryl. V, y,
Q2 and p are defined as in Formula (I). The palladium coupling
reaction is performed in an aprotic solvent such as toluene or dioxane,
in the presence of a palladium catalyst such as Pd(AcO)2 or
Pd(dba)3, in the presence of a suitable base such as
Cs2CO3 or t-BuONa and of a ligand, such as BINAP or Xantphos,
at a convenient temperature, either by conventional heating or under
microwave irradiation, for a period of time to ensure the completion of
the reaction. As an alternative, a copper coupling reaction may also be
used to prepare the (hetero)aryl derivatives. The reaction is performed
using an aprotic solvent, such as dioxane or DMF, in the presence of CuI,
an inorganic base such K3PO4 and MeNH(CH2)2NHMe as a
ligand, heating at a convenient temperature under traditional heating or
microwave irradiation, for a period of time to ensure the completion of
the reaction, which is typically about 25 minutes at about 175° C.
under microwave irradiation.

Preparation of Final Compounds in which X2 is Phenyl and Q2 is
NR1R2

[0114]The transformations of different functional groups Q2, present
in the final compounds prepared by scheme 2B, into different functional
groups present in other final compounds according to Formula (I), can be
performed by synthesis methods well known by the person skilled in the
art, such as reductive amination (Scheme 3A) or coupling reactions
(Scheme 3B). V, Y, R1 and R2 are defined as in Formula (I). R'
is an optional substitution of the phenyl-moiety as defined in Formula
(I), such as for example oxo; (C1-3)alkyloxy; halo; cyano; nitro;
formyl; hydroxy; amino; trifluoromethyl; mono- and
di((C1-3)alkyl)amino; carboxy; and thio.

Preparation of Final Compounds: Amides

[0116]When the --X2-Q2-moiety (or part of it) is an amide
derivative, preparation may be performed starting from the ester
derivative, which was synthesized by either methods shown in Schemes 2A
or 2B. Thus, basic hydrolysis of the ester group by standard and well
known reaction techniques, in an aprotic solvent such as THF or dioxane,
in the presence of an inorganic base, such as LiOH, KOH, or H2O, at
room temperature, for a period of time to ensure the completion of the
reaction, yields the corresponding carboxylic acid derivative. Amide
coupling of this carboxylic acid with different amines is performed using
standard reaction conditions, for example, using HATU as coupling agent,
in an aprotic solvent such as THF, DMF, CH2Cl2 (DCM), at room
temperature, for a period of time to ensure the completion of the
reaction. V, Y, X2, R1 and R2 are defined as in Formula
(I).

Preparation of Final Compounds: Modified Amines

[0118]When amino group is protected with a protecting group, deprotection
reaction may be carried out by synthetic methods well known to the person
skilled in the art. Transformations of the amino group of Q2,
present in the intermediate and final compounds, into different amino
derivatives of Q2, present in other final compounds according to
Formula (I) may be performed by synthetic methods well known by the
person skilled in the art, such as acylation, sulfonylation, urea
formation, alkylation or reductive amination reactions. Schemes 5A-E show
a general overview of such chemical transformations. V, Y, X2,
R1 and R2 are defined as in Formula (I).

Preparation of Final Compounds: Compounds Substituted on Carbon-6 of the
Pyrazinone-Core.

[0120]Reductive amination of the required starting material shown in the
scheme was performed in the presence of trimethylsilyl cyanide (TMSCN),
in an aprotic solvent, such as dichloromethane, and in the presence of a
reducing agent such as Ti(iprO)4, at a convenient temperature, for a
period of time to ensure the completion of the reaction, typically 16
hours at room temperature.

[0121]Cyclization of the intermediates was achieved by reaction with
oxalyl chloride in an aprotic solvent such as dichloroethane, at a
convenient temperature, for a period of time to ensure the completion of
the reaction, typically 60 hours at room temperature.

[0122]The alkylation reaction with intermediate V--CH2--YH was
performed in an aprotic solvent such as 1,2-dichloroethane, acetonitrile
or DMF, in the presence of an inorganic base, such as K2CO3,
Nα2CO3, NaOH, KOH, at a convenient temperature, either by
conventional heating or under microwave irradiation, for a period of time
to ensure the completion of the reaction, typically 30 minutes at
130° C. under microwave irradiation.

[0123]Hydrolysis was performed in acidic media, such as trifluoroacetic
acid, at a convenient temperature, either by conventional heating or
under microwave irradiation, for a period of time to ensure the
completion of the reaction, typically 15 minutes at 140° C. under
microwave irradiation. V, Y, X1 and p are defined as in Formula (I).

[0124]The transformations of different functional groups Q1, present
in the final compounds prepared by scheme 6, into different functional
groups present in other final compounds according to Formula (I), can be
performed by synthesis methods well known by the person skilled in the
art.

Pharmacology

[0125]The compounds according to the invention, in particular compounds
according to Formula (I), the pharmaceutically acceptable acid or base
addition salts thereof, a stereochemically isomeric form thereof, an
N-oxide form thereof or a quaternary ammonium salt thereof, have
surprisingly been shown to have a binding affinity towards
α2-adrenergic receptor, in particular towards
α2C-adrenergic receptor, in particular as an antagonist.

[0158]The invention therefore relates to a compound according to the
general Formula (I), a pharmaceutically acceptable acid or base addition
salt thereof, a stereochemically isomeric form thereof, an N-oxide form
thereof or a quaternary ammonium salt thereof, for use as a medicine.

[0159]The invention also relates to the use of a compound according to the
invention for the preparation of a medicament for the prevention and/or
treatment of central nervous system disorders, mood disorders, anxiety
disorders, stress-related disorders associated with depression and/or
anxiety, cognitive disorders, personality disorders, schizoaffective
disorders, Parkinson's disease, dementia of the Alzheimer's type, chronic
pain conditions, neurodegenerative diseases, addiction disorders, mood
disorders and sexual dysfunction.

[0160]The compounds according to the invention may be co-administered as
add-on treatment and/or prophylaxis in the above listed diseases in
combination with antidepressants, anxiolytics and/or antipsychotics which
are currently available or in development or which will become available
in the future, in particular to improve efficacy and/or onset of action.
It will be appreciated that the compounds of the present invention and
the other agents may be present as a combined preparation for
simultaneous, separate or sequential use for the prevention and/or
treatment of depression and/or anxiety. Such combined preparations may
be, for example, in the form of a twin pack. It will also be appreciated
that the compounds of the present invention and the other agents may be
administered as separate pharmaceutical compositions, either
simultaneously or sequentially.

[0161]The invention therefore relates to the use of the compounds
according to the invention as an add-on treatment in combination with one
or more other compounds selected from the group of antidepressants,
anxiolytics and antipsychotics.

[0172]The compounds according to the invention surprisingly also show a
high 5-HT-reuptake inhibition activity and are therefore very well suited
for use in the treatment and/or prophylaxis of depression. It is thought
that a 5-HT reuptake inhibitor with associated α2-adrenoceptor
antagonistic activity might be a new type of antidepressant, with a dual
action on the central noradrenergic and serotonergic neuronal systems.
The immediate effect on monoamine release of autoreceptor blockade may
accelerate the onset of action of such a compound, compared to currently
available drugs that require desensitization of the autoreceptors
involved in the feedback mechanism in order to become fully effective. In
addition, α2C-adrenoceptor antagonism improves sexual function
as shown by treatment with the α2C-adrenoceptor antagonist
yohimbine, thereby potentially reducing one of the side effects related
to 5-HT uptake inhibition and enhancement of NEergic neurotransmission
improves social function more effectively than SSRIs (J. Ignacio Andres
et al., J. Med. Chem. (2005), Vol. 48, 2054-2071).

Pharmaceutical Compositions

[0173]The invention also relates to a pharmaceutical composition
comprising a pharmaceutically acceptable carrier or diluent and, as
active ingredient, a therapeutically effective amount of a compound
according to the invention, in particular a compound according to Formula
(I), a pharmaceutically acceptable acid or base addition salt thereof, a
stereochemically isomeric form thereof, an N-oxide form thereof or a
quaternary ammonium salt thereof.

[0174]The compounds according to the invention, in particular the
compounds according to Formula (I), the pharmaceutically acceptable acid
or base addition salt thereof, a stereochemically isomeric form thereof,
an N-oxide form thereof or a quaternary ammonium salt thereof, or any
subgroup or combination thereof may be formulated into various
pharmaceutical forms for administration purposes. As appropriate
compositions there may be cited all compositions usually employed for
systemically administering drugs.

[0175]To prepare the pharmaceutical compositions of this invention, an
effective amount of the particular compound, optionally in addition salt
form, as the active ingredient is combined in intimate admixture with a
pharmaceutically acceptable carrier, which carrier may take a wide
variety of forms depending on the form of preparation desired for
administration. These pharmaceutical compositions are desirable in
unitary dosage form suitable, in particular, for administration orally,
rectally, percutaneously, by parenteral injection or by inhalation. For
example, in preparing the compositions in oral dosage form, any of the
usual pharmaceutical media may be employed such as, for example, water,
glycols, oils, alcohols and the like in the case of oral liquid
preparations such as suspensions, syrups, elixirs, emulsions and
solutions; or solid carriers such as starches, sugars, kaolin, diluents,
lubricants, binders, disintegrating agents and the like in the case of
powders, pills, capsules and tablets. Because of their ease in
administration, tablets and capsules represent the most advantageous oral
dosage unit forms in which case solid pharmaceutical carriers are
obviously employed. For parenteral compositions, the carrier will usually
comprise sterile water, at least in large part, though other ingredients,
for example, to aid solubility, may be included. Injectable solutions,
for example, may be prepared in which the carrier comprises saline
solution, glucose solution or a mixture of saline and glucose solution.
Injectable suspensions may also be prepared in which case appropriate
liquid carriers, suspending agents and the like may be employed. Also
included are solid form preparations that are intended to be converted,
shortly before use, to liquid form preparations. In the compositions
suitable for percutaneous administration, the carrier optionally
comprises a penetration enhancing agent and/or a suitable wetting agent,
optionally combined with suitable additives of any nature in minor
proportions, which additives do not introduce a significant deleterious
effect on the skin. Said additives may facilitate the administration to
the skin and/or may be helpful for preparing the desired compositions.
These compositions may be administered in various ways, e.g., as a
transdermal patch, as a spot-on, as an ointment.

[0176]It is especially advantageous to formulate the aforementioned
pharmaceutical compositions in unit dosage form for ease of
administration and uniformity of dosage. Unit dosage form as used herein
refers to physically discrete units suitable as unitary dosages, each
unit containing a predetermined quantity of active ingredient calculated
to produce the desired therapeutic effect in association with the
required pharmaceutical carrier. examples of such unit dosage forms are
tablets (including scored or coated tablets), capsules, pills, powder
packets, wafers, suppositories, injectable solutions or suspensions and
the like, and segregated multiples thereof. Since the compounds according
to the invention are potent orally administrable dopamine antagonists,
pharmaceutical compositions comprising said compounds for administration
orally are especially advantageous.

[0177]The invention also relates to a pharmaceutical composition
comprising the compounds according to the invention and one or more other
compounds selected from the group of antidepressants, anxiolytics and
antipsychotics as well as to the use of such a composition for the
manufacture of a medicament, in particular to improve efficacy and/or
onset of action in the treatment of depression and/or anxiety.

[0178]The following examples are intended to illustrate but not to limit
the scope of the present invention.

[0180]Microwave assisted reactions were performed in a single-mode
reactor: Emrys® Optimizer microwave reactor (Personal Chemistry A.B.,
currently Biotage). Description of the instrument can be found in
www.personalchemistry.com. And in a multimode reactor: MicroSYNTH
Labstation (Milestone, Inc.). Description of the instrument can be found
in www.milestonesci.com.

A. PREPARATION OF THE INTERMEDIATE COMPOUNDS

A1. Preparation of Intermediate Compound 3

a) Preparation of Intermediate Compound 1

[0182]2,3-Dichloropyrazine (10 g, 62.12 mmol) and
1-(phenylmethyl)-4-piperidinamine (13.73 mL, 67.12 mmol) were dissolved
in DMF (60 ml). Then Na2CO3 (10.09 g, 114.10 mmol) was added.
The reaction was stirred at 130° C. for 16 hours. The solid was
filtered off, washed with AcOEt and the solvent was evaporated till
dryness. The product was dissolved in AcOEt, washed with H2O and
brine, dried with MgSO4 and evaporated under vacuum. The product was
used without any further purification yielding 15 g of the desired
intermediate compound 1 (74%).

b) Preparation of Intermediate Compound 2

[0184]Intermediate compound 1 (7 g, 23.11 mmol) was dissolved in HCl (70
ml; 10%) and heated in a sealed tube at 110° C. for 16 hours. A
light brown solid was precipitated, it was filtered off, washed with
water and dried under vacuum yielding 4.57 g of the desired intermediate
compound 2 (70%).

c) Preparation of Intermediate Compound 3

[0186]Intermediate compound 2 (4.17 g, 14.66 mmol) was dissolved in
CH3OH (62 mL), then Pd/C (4.17 g; 10%) and 1,4-cyclohexadiene (27.96
mL, 293.2 mmol) were added. The reaction was heated in a sealed tube at
65° C. for 4 hours. The reaction was filtered over celite and the
solvent was evaporated till dryness yielding 2.69 g of the desired
intermediate compound 3 (94%).

A2. Preparation of Intermediate Compound 5

a) Preparation of Intermediate Compound 4

[0188]To a mixture of 4-formylbenzoic acid methyl ester (31.0 mmol) and
4-methoxybenzenemethanamine (34.1 mmol) in DCM (150 mL) was added
Ti-(i-PrOH)4 (3.1 mmol). The reaction was stirred for 2 hours at
room temperature; TMSCN (77.5 mmol) was added and the reaction was
stirred 24 hours at room temperature. The solvent was evaporated and the
oil was dissolved in Et2O (100 mL); then a solution of i-PrOH/HCl 6
N (10 mL) was added. The precipitate was filtered off and washed with
cold Et2O to yield 5.2 g of intermediate compound 4 as a white solid
(56%).

b) Preparation of Intermediate Compound 5

[0190]To a mixture of intermediate compound 4 (22 mmol) and DCE (200 mL),
ethanedioyl dichloride (66.3 mmol) was added. The reaction was stirred
for 4 days at room temperature. The crude was evaporated to dryness, to
afford 6 g of intermediate compound 5 as a yellow oil (60%). The crude
was used in the next step without purification.

A3. Preparation of Intermediate Compound 6

[0192]A mixture of 4-piperidinylcarbamic acid 1,1-dimethylethyl ester (25
mmol), 2-(bromomethyl)-naphtalene (25 mmol) and K2CO3 (52 mmol)
in CH3CN (50 ml) was heated to reflux for 3 hours. The organic phase
was filtered and the solvent was evaporated to obtain a white solid. The
solid was treated with a solution of DCM/TFA 8:2 and stirred for 1 hour.
The organic phase was evaporated to obtained 5 g (83%) of a white solid
of intermediate compound 6.

B. PREPARATION OF FINAL COMPOUNDS

[0193]Final compounds were prepared according to the following three
summary schemes.

B1. Preparation of Final Compound 5-01

[0195]Intermediate compound 3 (2 g, 10.269 mmol) was dissolved in DMF (60
ml), then naphthalene-2-carbaldehyde (4.82 g, 30.87 mmol) and
NaBH(OAc)3 (3.2 g, 15.45 mmol) was added. The reaction was stirred
at room temperature for 16 hours. The solvent was removed, the product
was dissolved in EtOAc, washed with NaHCO3 and brine and dried with
MgSO4. The solvent was evaporated till dryness and the product was
purified by open chromatography using DCM/CH3OH 9/1 as eluent,
yielding 3 g of the desired final compound 5-01 (87%).

B2. Preparation of Final Compound 1-67

a) Preparation of Final Compound 1-32

[0197]Final compound 5-01 (25 mg, 0.074 mmol), (3-bromopropyl)-carbamic
acid 1,1-dimethylethyl ester (0.112 mmol), and PS-TBD (76 mg, 0.222 mmol)
were suspended in CH3CN (1 ml). The reaction was heated in the
microwave at 130° C. for 20 minutes. The resin was filtered off,
and the filtrate was concentrated under vacuum. The resulting crude was
purified by HPLC yielding 0.029 g of the purified final compound 1-32
(80%).

b) Preparation of Final Compound 1-03

[0199]Final compound 1-32 (450 mg, 0.915 mmol) was dissolved in DCM (6
ml). Then TFA was added (6 ml). The reaction was stirred at room
temperature for 2 h. The solvent was concentrated under vacuum. The
resulting crude was dissolved in EtOAc and washed with an aqueous
solution of saturated K2CO3, then with NaCl (saturated), and
dried with MgSO4. The solvent was concentrated till dryness to yield
394 mg of the purified final compound 1-03 (97%).

c) Preparation of Final Compound 1-67

[0201]Final compound 1-03 (77 mg, 0.196 mmol) was dissolved in dry THF (3
ml). Benzaldehyde (30 μl, 0.295 mmol) and Ti(i-PrO)4 (112 mg,
0.392 mmol) were added. The reaction was stirred at room temperature for
16 hours. Then NaBH4 (23 mg, 0.59 mmol) and CH3CH2OH (1
ml) were added, stirring at room temperature for 8 hours. Then NH3
(aqueous solution) was added, a precipitate appears which was filtered
over celite and washed with Et2O. The organic layer was separated
and the remaining aqueous layer was extracted with Et2O. The
combined organic layers were treated with HCl (2N). The aqueous phase was
then treated with NaOH (2N) to PH 10-12, and washed with EtOAc
(3×10 ml). The organic layer was washed with brine, dried
(MgSO4) and evaporated till dryness. The resulting crude was
purified by open flash chromatography using DCM/(CH3OH/NH3) 9:1
to yield 30 mg of the purified final compound 1-67 (32%).

B3. Preparation of Final Compound 4-04

[0203]Final compound 5-01 (25 mg, 0.074 mmol) was dissolved in dry
CH3CN (1 ml), and then 2-(2-bromoethyl)-1,3-dioxolane (20.27 mg,
0.112 mmol) and PS-TBD (76 mg, 0.222 mmol) were added. The reaction
mixture was heated in the microwave at 130° C. for 20 minutes. The
resin was filtered off, and the filtrate concentrated under vacuum. The
resulting crude was purified by HPLC yielding 22 mg of the purified final
compound 4-04 (68%).

B4. Preparation of Final Compounds 1-24 and 1-45

a) Preparation of Final Compound 1-33

[0205]Final compound 5-01 (1 g, 2.99 mmol) was dissolved in 1,4-dioxane
(15 ml). [(4-bromophenyl)methyl]-carbamic acid 1,1-dimethylethyl ester
(1.02 g, 3.59 mmol), and CuI (114 mg, 0.598 mmol) were added, and the
mixture was stirred for 1 minute. Subsequently
N,N'-dimethyl-1,2-ethanediamine (127 μl, 1.19 mmol) was added, and the
mixture was stirred for 5 minutes. Finally K3PO4 (1.26 g, 5.98
mmol) was added. The mixture was heated at 110° C. in a seal tube
for 16 hours. The reaction mixture was filtered over celite, washed with
DCM and the solvent was evaporated till dryness. The crude product was
dissolved in DCM, washed with NH4Cl and brine and dried
(MgSO4). The solvent was evaporated under vacuum. The resulting
crude was purified by open flash chromatography in silicagel in
DCM/CH3OH (9.5/0.5) to yield 1.53 g of the final compound 1-33
(95%).

b) Preparation of Final Compound 1-01

[0207]Final compound 1-33 (1.41 g, 2.61 mmol) was dissolved in DCM (25
ml), then TFA (25 ml) was added. The mixture was stirred at room
temperature for 16 hours. The solvent was removed and the resulting crude
was dissolved in EtOAc and washed with K2CO3 (aqueous
saturated) and brine, and was then dried (MgSO4). The organic layer was
evaporated under vacuum, and the crude residue used without any further
purification, yielding 980 mg of the final compound 1-01 (86%).

c) Preparation of Final Compound 1-24

[0209]Butanoic acid (51.3 μl, 0.559 mmol), HATU (425 mg, 1.11 mmol) and
DIEA (292.11 μl, 1.67 mmol) were dissolved in DCM/DMF (80 ml, 2/1).
Then final compound 1-01 (270 mg, 0.615 mmol) was added. The reaction
mixture was stirred at room temperature for 16 hours. The solvent was
removed under vacuum. The crude was dissolved in DCM, washed with
NH4Cl, and brine, then dried (MgSO4). The solvent was concentrated
under reduced pressure and the resulting crude purified by open
chromatography in SiO2 with DCM/(CH3OH/NH3) (9.5/0.5) to
yield 95 mg of the final compound 1-24 (33%).

d) Preparation of Final Compound 1-45

[0210](111 mg, 0.135 mmol) was suspended in DCM (4 ml), and then
2-methoxyethanamine (101.39 mg, 1.35 mmol) was added. The reaction was
stirred at room temperature for 16 hours. The resin was filtered off, and
washed with DCM, CH3OH, THF and CH3CN. The resin was suspended
in CH3CN (4 ml). Final compound 1-01 (50 mg, 0.11 mmol) and
triethylamine (84 μl, 0.605 mmol) were added. The reaction was heated
at 65° C. for 16 hours. The resin was filtered off, washed with
CH3CN, DCM and CH3OH, and the solvent was evaporated till
dryness, to yield 58 mg of the final compound 1-45 (97%).

B5. Preparation of Final Compound 1-22

a) Preparation of Final Compound 5-10

[0212]Final compound 5-01 (1 g, 2.99 mmol), 4-bromobenzaldehyde (664 mg,
3.58 mmol) and CuI (114 mg, 5.98 mmol) were suspended in 1,4-dioxane (10
ml). The reaction was stirred for 1 minute, and then
N,N'-dimethyl-1,2-ethanediamine (131 μl, 1.2 mmol) was added while
stirring for 5 minutes more. K3PO4 (1.26 g, 5.98 mmol) was
added, while heating the mixture in a sealed tube at 110° C. for
16 hours. The reaction was filtered over celite, washed with DCM and the
solvent was evaporated till dryness. The crude compound was dissolved in
EtOAc, washed with H2O and brine, and dried (MgSO4). The
solvent was concentrated under vacuum, and the resulting crude purified
by HPLC to yield 220 mg of the final compound 5-10 (34%).

b) Preparation of Final Compound 1-22

[0214]Final compound 5-10 (250 mg, 0.570 mmol), 2-methoxyethanamine (1.14
mmol) and BH(OAc)3Na (181.20 mg, 0.855 mmol) were suspended in DCE
(50 ml). The reaction was stirred at room temperature for 16 hours. Then
NaHCO3 was added. The organic layer was separated and washed with
brine and dried (MgSO4). The solvent was concentrated under vacuum.
The resulting crude was purified by open chromatography in DCM/CH3OH
9/1 yielding 115 mg of the final compound 1-22 (40%).

B6. Preparation of Final Compound 6-07

[0216]Final compound 5-01 (140 mg, 0.419 mmol), 4-bromopyridine (0.502
mmol) and CuI (16 mg, 0.083 mmol) were suspended in 1,4-dioxane (4 ml).
The reaction was stirred for 1 minute at room temperature. Then
N,N'-dimethyl-1,2-ethanediamine (18 μl, 0.167 mmol) was added and the
mixture was stirred for 5 minutes more. Finally, K3PO4 (178 mg,
0.838 mmol) was added while heating the reaction mixture in a sealed tube
at 110° C. for 16 hours. The mixture was filtered over celite,
washed with DCM and the solvent evaporated till dryness. The crude was
dissolved then in DCM, washed with H2O and brine and dried
(MgSO4). The solvent was concentrated under reduced pressure. The
resulting crude was purified by open chromatography in
DCM/(CH3OH/NH3) 9.5/0.5 to yield 120 mg the final compound 6-07
(70%).

B7. Preparation of Final Compound 1-09

a) Preparation of Final Compound 3-05

[0218]Final compound 5-01 (180 mg, 0.538 mmol), 4-bromobenzoic acid methyl
ester (139 mg, 0.646 mmol) and CuI (21 mg, 0.17 mmol) were suspended in
1,4-dioxane (5 ml) and stirred at room temperature for 1 minute. Then
N,N'-dimethyl-1,2-ethanediamine (23 μl, 0.215 mmol) was added and the
mixture was stirred for 5 minutes more. Finally K3PO4 (228 mg,
1.07 mmol) was added, and the mixture was heated at 110° C. for 16
hours in a sealed tube. The crude product was filtered over celite,
washed with DCM and the solvent was concentrated under vacuum. The
resulting crude was washed with H2O, brine and dried (MgSO4).
The solvent was evaporated under reduced pressure and the resulting crude
was purified by open chromatography in DCM/(CH3OH/NH3) 9.5/0.5 to
yield 200 mg of the final compound 3-05 (80%).

b) Preparation of Final Compound 3-15

[0220]Final compound 3-05 (600 mg, 1.30 mmol), was suspended in CH3OH
(12 ml). Then LiOH (62.64 mg, 2.61 mmol) and H2O (2.4 ml) were added
and stirred for 16 hours at room temperature. The reaction was
neutralized with HCl 10%, the solvent was removed, and the product was
triturated with Et2O yielding 578 mg of the purified final compound
3-15 (quantitative).

c) Preparation of Final Compound 1-09

[0222]Final compound 3-15 (100 mg, 0.224 mmol) and HATU (100.83 mg, 0.265
mmol) were dissolved in DCM/DMF (11.5 ml, 2:1). Then 1-propanamine (12.06
mg, 0.204 mmol) was added. The reaction mixture was stirred at room
temperature for 16 hours. The solvent was removed under vacuum. The crude
was dissolved in DCM, washed with NH4Cl, and brine, then dried
(MgSO4). The solvent was concentrated under reduced pressure and the
resulting crude purified by open chromatography in SiO2 with
DCM/(CH3OH/NH3) 9.5/0.5 to yield 55 mg of final compound 1-09
(54%).

B8. Preparation of Final Compound 1-05

a) Preparation of Final Compound 5-12

[0224]Final compound 5-01 (400 mg, 1.19 mmol), 1-bromo-3-iodobenzene (508
mg, 1.79 mmol) and CuI (45 mg, 0.24 mmol) were suspended in 1,4-dioxane
(80 ml). The mixture was stirred at room temperature for 1 minute. Then
N,N'-dimethyl-1,2-ethanediamine (54 μl, 0.480 mmol) was added and the
mixture was stirred for 5 minutes more. K3PO4 (517 mg, 2.38
mmol) was added, and the mixture was heated at 110° C. for 16
hours in a sealed tube. The crude product was filtered over celite,
washed with DCM and the solvent was concentrated under vacuum. The
resulting crude was washed with H2O, brine and dried (MgSO4).
The solvent was evaporated under reduced pressure and the resulting crude
was purified by open chromatography in DCM/(CH3OH/NH3) 9.5/0.5 to
yield 120 mg of the final compound 5-12 (21%).

b) Preparation of Final Compound 1-05

[0226]Final compound 5-12 (810 mg, 0.16 mmol), 1-butanamine (24 μl,
0.24 mmol), CuI (6 mg, 0.032 mmol) and L-proline. TFA (15 mg, 0.128 mmol)
were suspended in DMSO (1 ml). Then K2CO3 (44 mg, 0.32 mmol)
was added and the mixture was heated to 80° C. for 24 hours in a
sealed tube. The crude product was filtered over celite, washed with DCM
and the solvent was concentrated under vacuum. The resulting crude was
washed with H2O, brine and dried (MgSO4). The solvent was
evaporated under reduced pressure and the resulting crude was purified by
open chromatography in DCM/(CH3OH/NH3) 50/1 to yield 40 mg of
the final compound 1-05 (52%).

B9. Preparation of Final Compound 8-05

a) Preparation of Final Compound 8-04

[0228]To a mixture of intermediate compound 5 (0.756 mmol) and
intermediate compound 6 (0.787 mmol) in toluene/CH3OH (9/1) (2 ml),
K2CO3 (105 mmol) was added. The reaction was heated under
microwave irradiation at 130° C. for 30 minutes. The solvent was
evaporated and the oil was purified by column chromatography (eluent
DCM/CH3OH 9/1); selected fractions were collected and their solvent
evaporated yielding 0.39 g (88%) of final compound 8-04 as a white solid.

b) Preparation of Final Compound 8-03

[0230]To a mixture of final compound 8-04 (0.32 mmol) in THF (20 mL),
DIBAL/THF (3.2 mmol) was added at -78° C. The reaction was stirred
to room temperature for 24 hours. The crude was filtered over celite and
the solvent was evaporated; the residue was treated with a solution of
NaOH (4 mL) 4 N and DCM (20 mL). The crude were stirred for 10 minutes
and the final compound was extracted with DCM (3×5 mL). The organic
solvent was evaporated and the oil was purified by column chromatography
(eluent DCM/CH3OH 9/1); selected fractions were collected and their
solvent evaporated, yielding 0.125 g (65%) of final compound 8-03 as a
white solid.

c) Preparation of Final Compound 8-16

[0232]To a mixture of final compound 8-03 (0.336 mmol) in DCM (10 mL)
methanesulfonyl chloride (0.37 mmol) and DiPEA (0.73 mmol) was added at
0° C. The reaction mixture was stirred at room temperature for 3
hours. The solvent was evaporated and the residue was used for the next
step without any purification. After the solvent was removed, the final
compound 8-16 was obtained as a yellow oil.

d) Preparation of Final Compound 8-05

[0234]A mixture of final compound 8-16 (0.2971 mmol), propylamine (0.3268
mmol), and K2CO3 (0.653 mmol) in CH3CN (2 mL) was heated
under microwave irradiation at 130° C. for 10 minutes. The organic
solvent was evaporated and the oil was purified by column chromatography
(eluent DCM/CH3OH 9/1); selected fractions were collected and their
solvent evaporated, yielding 0.135 g (71%) of final compound 8-05 as an
oil.

B10. Preparation of Final Compound 7-02

[0236]A mixture of final compound 8-05 (0.16 mmol) in TFA (2 mL) was
heated under microwave irradiation at 130° C. for 15 minutes. The
organic solvent was evaporated and the oil was purified by column
chromatography (eluent DCM/CH3OH 9/1); selected fractions were
collected and their solvent was evaporated, yielding 0.05 g (56%) of
final compound 7-02.

[0237]The following compounds were prepared according to the above
examples, schemes and procedures.

[0238]The interaction of the compounds of Formula (I) with
α2C-adrenoceptor receptors was assessed in in vitro
radioligand binding experiments. In general, a low concentration of a
radioligand with a high binding affinity for a particular receptor or
transporter is incubated with a sample of a tissue preparation enriched
in a particular receptor or transporter or with a preparation of cells
expressing cloned human receptors in a buffered medium. During the
incubation, the radioligand binds to the receptor or transporter. When
equilibrium of binding is reached, the receptor bound radioactivity is
separated from the non-bound radioactivity, and the receptor- or
transporter-bound activity is counted. The interaction of the test
compounds with the receptor is assessed in competition binding
experiments. Various concentrations of the test compound are added to the
incubation mixture containing the receptor- or transporter preparation
and the radioligand. The test compound in proportion to its binding
affinity and its concentration inhibits binding of the radioligand. The
radioligand used for hα2C, hα2C and hα2C
receptor binding was [3H]-raulwolscine.

Example C.1

Binding Experiment for α2C-Adrenoceptor

Cell Culture and Membrane Preparation

[0239]CHO cells, stabile transfected with human adrenergic-α2A,
-α2B or α2C receptor cDNA, were cultured in
Dulbecco's Modified Eagle's Medium (DMEM)/Nutrient mixture Ham's F12
(ratio 1:1)(Gibco, Gent-Belgium) supplemented with 10% heat inactivated
fetal calf serum (Life Technologies, Merelbeke-Belgium) and antibiotics
(100 IU/ml penicillin G, 100 μg/ml streptomycin sulphate, 110 μg/ml
pyruvic acid and 100 μg/ml L-glutamine). One day before collection,
cells were induced with 5 mM sodiumbutyrate. Upon 80-90% of confluence,
cells were scraped in phosphate buffered saline without Ca2+ and
Mg2+ and collected by centrifugation at 1500×g for 10 minutes.
The cells were homogenised in Tris-HCl 50 mM using an Ultraturrax
homogenizer and centrifuged for 10 minutes at 23,500×g. The pellet
was washed once by resuspension and rehomogenization and the final pellet
was resuspended in Tris-HCl, divided in 1 ml aliquots and stored at
-70° C.

Binding Experiment for α2-Adrenergic Receptor Subtypes

[0240]Membranes were thawed and re-homogenized in incubation buffer
(glycylglycine 25 mM, pH 8.0). In a total volume of 500 μl, 2-10 μg
protein was incubated with [3H]raulwolscine (NET-722) (New England
Nuclear, USA) (1 nM final concentration) with or without competitor for
60 minutes at 25° C. followed by rapid filtration over GF/B filter
using a Filtermate196 harvester (Packard, Meriden, Conn.). Filters were
rinsed extensively with ice-cold rinsing buffer (Tris-HCl 50 mM pH 7.4).
Filter-bound radioactivity was determined by scintillation counting in a
Topcount (Packard, Meriden, Conn.) and results were expressed as counts
per minute (cpm). Non-specific binding was determined in the presence of
1 μM oxymetazoline for hα2A- and hα2B receptors
and 1 μM spiroxatrine for hα2C receptors.

Binding Experiment for the 5HT-Transporter

[0241]Human platelet membranes (Oceanix Biosciences Corporation, Hanover,
Md., USA) were thawed, diluted in buffer (Tris-HCl 50 mM, 120 mM NaCl and
5 mM KCl) and quickly (max 3 s) homogenised with an Ultraturrax
homogenizer. In a total volume of 250 μL, 50-100 μg protein was
incubated with [3H]paroxetine (NET-869) (New England Nuclear, USA)
(0.5 nM final concentration) with or without competitor for 60 min at
25° C. Incubation was stopped by rapid filtration of the
incubation mixture over GF/B filters, pre-wetted with 0.1%
polyethyleneamine, using a Filtermate196 harvester (Packard, Meriden,
Conn.). Filters were rinsed extensively with ice-cold buffer and
radioactivity on the filters was counted in a Topcount liquid
scintillation counter (Packard, Meriden, Conn.). Data were expressed as
cpm. Imipramine (at 1 μM final concentration) was used to determine
the non-specific binding.

Data Analysis and Results

[0242]Data from assays in the presence of compound were calculated as a
percentage of total binding measured in the absence of test compound.
Inhibition curves, plotting percent of total binding versus the log value
of the concentration of the test compound, were automatically generated,
and sigmoidal inhibition curves were fitted using non-linear regression.
The pIC50 values of test compounds were derived from individual
curves.

[0243]All compounds according to Formula (I) produced an inhibition at
least at the hα2C site (but often also at the hα2A
and hα2B-sites) of more than 50% (pIC50) at a test
concentration ranging between 10-6 M and 10-9 M in a
concentration-dependent manner.

[0244]For a selected number of compounds, covering most of the various
embodiments of Formula (I), the results of the in vitro studies are given
in Table 10.

[0245]Active ingredient" (a.i.) as used throughout these examples relates
to a compound of formula (I), the pharmaceutically acceptable acid or
base addition salts thereof, the stereochemically isomeric forms thereof,
the N-oxide form thereof, a quaternary ammonium salt thereof and prodrugs
thereof.

Example D.1

Oral Drops

[0246]500 Grams of the a.i. is dissolved in 0.5 l of 2-hydroxypropanoic
acid and 1.5 l of the polyethylene glycol at 60˜80° C. After
cooling to 30˜40° C. there are added 35 l of polyethylene
glycol and the mixture is stirred well. Then there is added a solution of
1750 grams of sodium saccharin in 2.5 l of purified water and while
stirring there are added 2.5 l of cocoa flavor and polyethylene glycol
q.s. to a volume of 50 l, providing an oral drop solution comprising 10
mg/ml of a.i. The resulting solution is filled into suitable containers.

Example D.2

Oral Solution

[0247]9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl
4-hydroxybenzoate are dissolved in 4 l of boiling purified water. In 3 l
of this solution are dissolved first 10 grams of 2,3-dihydroxybutanedioic
acid and thereafter 20 grams of the a.i. The latter solution is combined
with the remaining part of the former solution and 12 l
1,2,3-propanetriol and 3 l of sorbitol 70% solution are added thereto. 40
Grams of sodium saccharin are dissolved in 0.5 l of water and 2 ml of
raspberry and 2 ml of gooseberry essence are added. The latter solution
is combined with the former, water is added q.s. to a volume of 20 l
providing an oral solution comprising 5 mg of the active ingredient per
teaspoonful (5 ml). The resulting solution is filled in suitable
containers.

Example D.3

Film-Coated Tablets

Preparation of Tablet Core

[0248]A mixture of 100 grams of the a.i., 570 grams lactose and 200 grams
starch is mixed well and thereafter humidified with a solution of 5 grams
sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml
of water. The wet powder mixture is sieved, dried and sieved again. Then
there is added 100 grams microcrystalline cellulose and 15 grams
hydrogenated vegetable oil. The whole is mixed well and compressed into
tablets, giving 10,000 tablets, each containing 10 mg of the active
ingredient.

Coating

[0249]To a solution of 10 grams methyl cellulose in 75 ml of denaturated
ethanol there is added a solution of 5 grams of ethyl cellulose in 150 ml
of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5
ml 1,2,3-propanetriol. 10 grams of polyethylene glycol is molten and
dissolved in 75 ml of dichloromethane. The latter solution is added to
the former and then there are added 2.5 grams of magnesium octadecanoate,
5 grams of polyvinylpyrrolidone and 30 ml of concentrated color
suspension and the whole is homogenated. The tablet cores are coated with
the thus obtained mixture in a coating apparatus.

Example D.4

Injectable Solution

[0250]1.8 grams methyl 4-hydroxybenzoate and 0.2 grams propyl
4-hydroxybenzoate are dissolved in about 0.5 l of boiling water for
injection. After cooling to about 50° C. there are added while
stirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of
the a.i. The solution is cooled to room temperature and supplemented with
water for injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of
a.i. The solution is sterilized by filtration and filled in sterile
containers.

Physico-Chemical Data

General Procedure

[0251]The HPLC gradient was supplied by a HP 1100 from Agilent
Technologies comprising a quaternary pump with degasser, an autosampler,
a column oven (set at 40° C.) and diode-array detector (DAD). Flow
from the column was split to a MS detector. The MS detector was
configured with an electrospray ionization source. Nitrogen was used as
the nebulizer gas. The source temperature was maintained at 140°
C. Data acquisition was performed with MassLynx-Openlynx software.

E.1 LCMS

Procedure 1

[0252]In addition to the general procedure: Reversed phase HPLC was
carried out on an XDB-C18 cartridge (3.5 μm, 4.6×30 mm) from
Agilent, with a flow rate of 1 ml/min. The gradient conditions used are:
80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.0 minutes, to 100% B at 6.5 minutes,
kept till 7.0 minutes and equilibrated to initial conditions at 7.6
minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass
spectra (Time of Flight, TOF) were acquired by scanning from 100 to 750,
for example in 1.0 second using a dwell time of 1.0 second. The capillary
needle voltage was 2.5 kV for positive ionization mode and 2.9 kV for
negative ionization mode. The cone voltage was 20 V for both positive and
negative ionization modes. Leucine-enkephaline was the standard substance
used for the lock mass calibration.

E.2 LCMS

Procedure 2

[0253]In addition to the general procedure: Reversed phase HPLC was
carried out on an XDB-C18 cartridge (3.5 μm, 4.6×30 mm) from
Agilent, with a flow rate of 1 ml/min. The gradient conditions used are:
80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.0 minutes, to 100% B at 6.5 minutes,
kept till 7.0 minutes and equilibrated to initial conditions at 7.6
minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass
spectra (Time of Flight, TOF) were acquired only in positive ionization
mode by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1
seconds. The capillary needle voltage was 2.5 kV and the cone voltage was
20 V. Leucine-enkephaline was the standard substance used for the lock
mass calibration.

E.3 LCMS

Procedure 3

[0254]In addition to the general procedure: Reversed phase HPLC was
carried out on an XDB-C18 cartridge (3.5 μm, 4.6×30 mm) from
Agilent, with a flow rate of 1 ml/min. The gradient conditions used are:
80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.0 minutes, to 100% B at 6.5 minutes,
kept till 7.0 minutes and equilibrated to initial conditions at 7.6
minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass
spectra (Time of Flight, TOF) were acquired by scanning from 100 to 750
in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needle
voltage was 2.5 kV for positive ionization mode and 2.9 kV for negative
ionization mode. The cone voltage was 20 V for both positive and negative
ionization modes. Leucine-enkephaline was the standard substance used for
the lock mass calibration.

E.4 LCMS

Procedure 4

[0255]In addition to the general procedure: Reversed phase HPLC was
carried out on an ACE-C18 column (3.0 μm, 4.6×30 mm) from
Advanced Chromatography Technologies, with a flow rate of 1.5 ml/min. The
gradient conditions used are: 80% A (0.5 g/l ammonium acetate solution),
10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes,
to 100% B at 7 minutes and equilibrated to initial conditions at 7.5
minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass
spectra (Time of Flight, TOF) were acquired only in positive ionization
mode by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1
seconds. The capillary needle voltage was 2.5 kV for positive ionization
mode and the cone voltage was 20 V. Leucine-enkephaline was the standard
substance used for the lock mass calibration.

E.5 LCMS

Procedure 5

[0256]In addition to the general procedure: Same as procedure 4 but an
injection volume of 10 μL was used.

E.6 LCMS

Procedure 6

[0257]In addition to the general procedure: Reversed phase HPLC was
carried out on an XDB-C8 cartridge (3.5 μm, 4.6×30 mm) from
Agilent, with a flow rate of 1 ml/min. The gradient conditions used are:
80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.0 minutes, to 100% B at 6.5 minutes,
kept till 7.0 minutes and equilibrated to initial conditions at 7.6
minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass
spectra (Time of Flight, TOF) were acquired by scanning from 100 to 750
in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needle
voltage was 2.5 kV for positive ionization mode and 2.9 kV for negative
ionization mode. The cone voltage was 20 V for both positive and negative
ionization modes. Leucine-enkephaline was the standard substance used for
the lock mass calibration.

E.7 LCMS

Procedure 7

[0258]In addition to the general procedure: Same as procedure 2 but an
injection volume of 10 μL was used.

E.8 LCMS

Procedure 8

[0259]In addition to the general procedure: Reversed phase HPLC was
carried out on an XDB-C18 cartridge (3.5 μm, 4.6×30 mm) from
Agilent, with a flow rate of 1 ml/min. The gradient conditions used are:
80% A (0.5 g/l ammonium acetate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.0 minutes, to 100% B at 6.5 minutes,
kept till 7.0 minutes and equilibrated to initial conditions at 7.6
minutes until 9.0 minutes. Injection volume 5 μl. Low-resolution mass
spectra (ZQ detector, quadrupole) were acquired by scanning from 100 to
1000 in 1.0 second using a dwell time of 0.3 seconds. The capillary
needle voltage was 3 kV. The cone voltage was 20 V and 50 V for positive
ionization mode and 20 V for negative ionization mode.

E.9 LCMS

Procedure 9

[0260]In addition to the general procedure: Reversed phase HPLC was
carried out on an XT-C18 column (3.5 μm, 4.6×30 mm) from Waters,
with a flow rate of 1 ml/min. The gradient conditions used are: 80% A (1
g/l ammonium bicarbonate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.0 minutes, to 100% B at 6.5 minutes,
kept till 7.0 minutes and equilibrated to initial conditions at 7.6
minutes until 9.0 minutes. Injection volume 5 μl. High-resolution mass
spectra (Time of Flight, TOF) were acquired only in positive ionization
mode by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1
seconds. The capillary needle voltage was 2.5 kV and the cone voltage was
20 V. Leucine-enkephaline was the standard substance used for the lock
mass calibration.

E.10 Melting Points

[0261]For a number of compounds, melting points were determined in open
capillary tubes on a Mettler FP62 apparatus. Melting points were measured
with a temperature gradient of 3 or 10° C./minute. Maximum
temperature was 300° C. The melting point was read from a digital
display.